Abstract: Computational chemistry grew in a new era of desktop modeling, which coincided with a growing demand for modeling software, especially from the pharmaceutical industry. Parameterization of models in computational chemistry is an arduous enterprise, and we argue that this activity leads, in this specific context, to tensions among scientists regarding the lack of epistemic transparency of parameterized methods and the software implementing them. To explicit these tensions, we rely on a corpus which is suited for revealing them, namely the Computational Chemistry mailing List (CCL), a professional scientific discussion forum. We relate one flame war from this corpus in order to assess in detail the relationships between modeling methods, parameterization, software and the various forms of their enclosure or disclosure. Our claim is that parameterization issues are a source of epistemic opacity and that this opacity is entangled in methods and software alike. Models and software must be ...
ACS Short Course Computational Chemistry and Computer-Assisted Drug Design: Practical Approaches 230th ACS National Meeting Washington Convention Center, Washington, DC Friday-Saturday, August 26-27, 2005 This introductory level course is designed for organic chemists, pharmaceutical chemists, and biochemists who are interested in learning more about computational and combinatorial methods, or scientists who need to develop a working knowledge of the fundamentals and need to understand the concepts and terminology of this rapidly developing area. Program Overview of Computational Chemistry and Computer-Assisted Drug Design Molecular Mechanics: Background, Development, Concepts, Force Fields Conformational Searching Molecular Dynamics Simulations: Background, Development, Concepts, and Applications Protein Structure Prediction Overview of Quantum Chemistry Methods and Its Application to Drug Design DNA and Protein Sequence and Structure Analysis Drug Design Methods and Pharmacophore Design QSAR ...
Around 20% of all the computational chemistry papers published in 2014 emanate from the USA, more than double the closest competitor, China. The top ten nations in terms of publications are USA 19.5%, China 9.3%, Germany 6.1%, India 4.3%, France 4.0%, Italy 3.8%, Spain 3.7%, England 3.6%, Japan 2.7% and Canada 2.4% - making nearly 60% of the total output. A decade ago in 2004 the ten most prolific countries accounted for around 87% of total output, which indicates that recent years have witnessed a greater global involvement in computational chemistry. Noticeable trends are seen in individual nations share of the computational chemistry pie, with the USA and some European nations effectively halving their fraction of papers between 2004 and 2014, with Chinas output nearly doubling from 5.4% in 2004 to 9.3% in 2014 and the emergence of India from outside the top ten into fourth place in 2014. It should be borne in mind that the globalization of science will inevitably lead to some over counting ...
van der Waals interactions are important to protein stability and function. These interactions are usually identified empirically based on protein 3D structures. In this work, we performed a solution nuclear magnetic resonance (NMR) spectroscopy study of van der Waals interactions by detecting the through-space (vdw)J(CC)-coupling between protein aliphatic side chain groups. Specifically, (vdw)J(CC)-coupling values up to similar to 0.5 Hz were obtained between the methyl and nearby aliphatic groups in protein GB3, providing direct experimental evidence for the van der Waals interactions. Quantum mechanical calculations suggest that the J-coupling is correlated with the exchange-repulsion term of van der Waals interaction. NMR detection of (vdw)J(CC)-coupling offers a new tool to characterize such interactions in proteins ...
Protein structures provide a valuable resource for rational drug design. For a protein with no known ligand, computational tools can predict surface pockets that are of suitable size and shape to accommodate a complementary small-molecule drug. However, pocket prediction against single static structures may miss features of pockets that arise from proteins dynamic behaviour. In particular, ligand-binding conformations can be observed as transiently populated states of the apo protein, so it is possible to gain insight into ligand-bound forms by considering conformational variation in apo proteins. This variation can be explored by considering sets of related structures: computationally generated conformers, solution NMR ensembles, multiple crystal structures, homologues or homology models. It is non-trivial to compare pockets, either from different programs or across sets of structures. For a single structure, difficulties arise in defining particular pockets boundaries. For a set of conformationally
A SERVICE to enable researchers to outsource computational chemistry has been introduced by Cresset, a software company. Its CompChem on Demand offering supplies computational chemistry services on a day-by-day basis, without long-term commitment.. Users of the service can purchase service days in advance, at a discounted on the daily rate, and use these as needed. Cressets service team, under director of consulting Dr Martin Slater, offers a range of skills including the design of both large and small molecular libraries, lead optimisation, and structure-activity relationship (SAR) analysis.. The services provided will make use of Cressets commercially-available software, if appropriate, as well as the companys in-house proprietary code and applications.. The financial reality of drug discovery demands that researchers minimise costs while maximising throughput and efficiency, said Dr Robert Scoffin, CEO of Cresset. Through our on-demand consulting service, customers are able to match ...
Check out our new paper and video on Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction. ...
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16.08.28 Theory and Applications of Computational Chemistry 2016, Computational Chemistry List, Resource for Computational Chemists, molecular modeling, and associated archives
17.11.06 Computational Chemistry and Biology Opportunities at D. E. Shaw Research, Computational Chemistry List, Resource for Computational Chemists, molecular modeling, and associated archives
This thesis discusses recent results using the Associative-memory, Water-mediated, Structure and Energy Model (AWSEM), an optimized, coarse-grained molecular dynamics model. AWSEM and its membrane protein extension, AWSEM-membrane, are capable of de novo protein structure prediction and through the use of statistical estimators, allow construction of free energy landscapes which can provide insight about the dynamics of protein systems. We review the origins of energy landscape theory and how one can learn energy functions using the results of spin glass-inspired statistical mechanics models. We explore the similarities and differences between the energy landscapes of proteins that have been selected by nature and those of some proteins designed by humans. We also study how robust the folding of these designs would be to the simplification of the sequences using fewer amino acid types. Using an optimized extension of AWSEM, AWSEM-membrane, we explore the hypothesis that the folding landscapes of ...
A foreword from Professor Kendall N. Houk for the Applied Computational Chemistry themed issue of Chemical Society Reviews. Applied Computational Chemistry
TY - CHAP. T1 - Low frequency motions in proteins secondary structures. Molecular dynamics studies on carboxy terminal fragment of L7/L12 ribosomal protein. AU - Tapia, O.. AU - Nilsson, O.. AU - Campillo, M.. AU - Aqvist, J.. AU - Horjales, E.. PY - 1990/1/1. Y1 - 1990/1/1. M3 - Chapter. SN - 0-940030-30-6. VL - 2. T3 - DNA Protein complexes & Proteins. SP - 147. EP - 170. BT - Structure & methods: proceedings of the Sixth Conversation in the Discipline Biomolecular Stereodynamics. Volume 2 DNA protein complexes & proteins. A2 - Ramaswamy H. Sarma, null. A2 - Mutki H. Sarma, null. PB - Adenine Press. CY - Schenectady (US). ER - ...
The structure of a protein ultimately determines its function; therefore, knowledge of three-dimensional structure is essential for understanding its function and mechanism of action. The two most common methods for determining protein structure are x-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy. These methods are quite successful but can be very time-intensive and costly. An alternative method is protein structure prediction, where structure is computationally predicted from amino acid sequence. As opposed to x-ray crystallography and NMR spectroscopy, protein structure prediction is not encumbered by potential experimental problems. In this research, we attempted to determine if certain protein structure features, known as tertiary contacts, can improve the prediction of protein three-dimensional structure. By calculating and analyzing sequence homology and related values, it was shown that tertiary contacts, which typically are long-range amino acid interactions
Successful protein structure prediction requires accurate low-resolution scoring functions so that protein main chain conformations that are close to the native can be identified. Once that is accomplished, a more detailed and time-consuming treatment to produce all-atom models can be undertaken. The earliest low-resolution scoring used simple distance-based contact potentials, but more recently, the relative orientations of interacting amino acids have been taken into account to improve performance. We developed a new knowledge-based scoring function, LoCo, that locates the interaction partners of each individual residue within a local coordinate system based only on the position of its main chain N, Cα and C atoms. LoCo was trained on a large set of experimentally determined structures and optimized using standard sets of modeled structures, or decoys. No structure used to train or optimize the function was included among those used to test it. When tested against 29 other published main chain
The Computational Chemistry and Molecular Modeling Support Group helps intramural researchers create structural models of biomolecules when X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, or mass spectrometry data isnt available. By combining computer-based techniques with experimental and theoretical structural information, the group is able to develop structures that mimic the behavior of molecules or molecular reactions ...
TY - JOUR. T1 - Secondary structure prediction of β-subunits of the gonadotropin-thyrotropin family from its aligned sequences using environment-dependent amino-acid substitution tables and conformational propensities. AU - Wako, Hiroshi. AU - Ishii, Susumu. PY - 1995/2/22. Y1 - 1995/2/22. N2 - The secondary structures of β-subunits of the glycoprotein hormone family, LH (luteinizing hormone), CG (chorionic gonadotropin), FSH (follicle stimulating hormone), TSH (thyroid stimulating hormone), and GTH I/GTH II (two types of fish gonadotropins), are predicted by comparing an amino-acid substitution pattern at equivalent sites in their aligned sequences with environment-dependent amino-acid substitution tables and conformational propensities calculated from other protein families whose three-dimensional structures are known. According to the prediction results, together with other structural information obtained from experiments, the following points come up as important structural features of the ...
Main Page of the Computational Chemistry Group. Scientific interests: Free Energy calculations, QM/MM method, PAW-method, Biological Nitrogen Fixation by Nitrogenase, sodium nitroprusside
Blind protein structure predictions from CASP3 and CASP4. A: Left, crystal structure of the MarA transcription factor bound to DNA; right, our best submitted model in CASP3. Despite many incorrect details, the overall fold is predicted with sufficient accuracy to allow insights into the mode of DNA binding. B: Left, the crystal structure of bacteriocin AS-48; middle, our best submitted model in CASP4; right, a structurally and functionally related protein (NK-lysin) identified using this model in a structure-based search of the Protein Data Bank (PDB). The structural and functional similarity is not recognizable using sequence comparison methods (the identity between the two sequences is only 5 percent). C: Left, crystal structure of the second domain of MutS; middle, our best submitted model for this domain in CASP4; right, a structurally related protein (RuvC) with a related function recognized using the model in a structure-based search of the PDB. The similarity was not recognized using ...
Several methods to assess the (dis)similarity of protein structures objectively are described, some of which, when applied to non-crystallographically related protein models, are able to discriminate between significant differences and random noise. Some of these methods have been used to investigate a sample of several hundred protein structures which have been solved by means of X-ray crystallography in order to investigate the extent to which non-crystallographically related protein models differ from one another. It is shown that the extent of such differences is largely dependent on the resolution of the data used for the determination and refinement of the structure and, measured by some statistics, even varies essentially linearly with the resolution. The implications of these findings for the strategies used to refine structures with non-crystallographic symmetry, in particular at low resolution, are discussed. Finally, two examples are given of recent structure determinations from ...
diss/z2006/0801 Prediction of protonation states in ligand-protein complexes upon ligand binding Recent hardware development increase the computing power, in consequence many biological and chemical processes can now be successfully modelled in a way which was not to imagine 20 years ago. Examples of such processes are molecular dynamics studies of large biomolecules, the prediction of free energy of binding for protein-ligand complexes, investigations of reaction paths in enzymes, to mention only a few. One issue which is still unresolved concerns the accurate estimation of protonation states in protein-ligand complexes. In this thesis, we present the development of a novel charge assignment procedure named PEOE_PB (Partial Equalisation of Orbital Electronegativities - optimized for Poisson-Boltzmann calculations), which represents a method for the assignment of atomic partial charges. It works reliably with both proteins and small organic molecules using a consistent approach. Such charges are ...
Protein dynamics play a crucial role in function, catalytic activity, and pathogenesis. Consequently, there is great interest in computational methods that probe the conformational fluctuations of a protein. However, molecular dynamics simulations are computationally costly and therefore are often limited to comparatively short timescales. TYPHON is a probabilistic method to explore the conformational space of proteins under the guidance of a sophisticated probabilistic model of local structure and a given set of restraints that represent nonlocal interactions, such as hydrogen bonds or disulfide bridges. The choice of the restraints themselves is heuristic, but the resulting probabilistic model is well-defined and rigorous. Conceptually, TYPHON constitutes a null model of conformational fluctuations under a given set of restraints. We demonstrate that TYPHON can provide information on conformational fluctuations that is in correspondence with experimental measurements. TYPHON provides a ...
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The School of Chemistry has developed a particular strength in Theoretical and Computational Chemistry, with a research group dedicated to this exciting area of study. As part of the Chemistry (PhD/MPhil) programme, students can conduct their research within this group.
Although conformational changes in TCRs and peptide Ags presented by MHC protein (pMHC) molecules often occur upon binding, their relationship to intrinsic flexibility and role in ligand selectivity are poorly understood. In this study, we used nuclear magnetic resonance to study TCR-pMHC binding, examining recognition of the QL9/H-2Ld complex by the 2C TCR. Although the majority of the CDR loops of the 2C TCR rigidify upon binding, the CDR3β loop remains mobile within the TCR-pMHC interface. Remarkably, the region of the QL9 peptide that interfaces with CDR3β is also mobile in the free pMHC and in the TCR-pMHC complex. Determination of conformational exchange kinetics revealed that the motions of CDR3β and QL9 are closely matched. The matching of conformational exchange in the free proteins and its persistence in the complex enhances the thermodynamic and kinetic stability of the TCR-pMHC complex and provides a mechanism for facile binding. We thus propose that matching of structural ...
About the courseThe three primary activities in theoretical and computational chemistry are development of new theory, implementation of methods as reliable software, and application of such methods to a host of challenges in chemical and related sciences. The MSc aims to train new research students to be able to deliver these outcomes.
Computational chemistry methods have become increasingly important in recent years, as manifested by their rapidly extending applications in a large number of diverse fields. The ever-increasing size
The molecular structures of triisopropoxystibane, Sb((OPr)-Pr-i)(3), and chlorodiisopropoxystibane, SbCl((OPr)-Pr-i)(2), were determined in the solid state by single crystal X-ray diffraction. Sb((OPr)-Pr-i)(3) forms discrete centrosymmetric dimers in the solid state via Sb . . .O-Sb interactions, leading to pseudo trigonal bipyramidal configurations of the four co-ordinate Sb atoms, while SbCl((OPr)-Pr-i)(2) forms chains via Sb . . .O-Sb and Sb . . . Cl-Sb bridges, resulting in five-co-ordinate Sb atoms with pseudo octahedral configurations. Comparison of the solid state structures and the density functional optimized molecular structures of Sb(OMe)(3), SbCl(OMe)(2) and their dimers revealed a steady increase of the average Sb-O bond lengths with the co-ordination number of Sb, and mutual trans effects of the ligands. Standard enthalpies of dimer formation from density functional calculations are -23.8 and -69.7 kJ mol(-1) for [Sb-2(mu -OMe)(2)(OMe)(4)] and [Sb2Cl2(mu -OMe)(2)(OMe)(2)], ...
To understand the way a protein functions it is important to consider its cellular environment. About 25 % of genes encode membrane proteins, and furthermore membrane proteins are targets for ~50 % of marketed drugs. Signalling mechanisms of membrane receptors involve subtle conformational changes of these proteins [1]. Therefore it is of paramount importance from a biological and pharmaceutical point of view to elucidate the dynamics of these macromolecules in their native lipid environment. The use of molecular dynamics (MD) simulations represents the first natural choice to investigate such functional dynamics [2,3], providing an atomistic description of the interactions at work. Furthermore, the growing number of experimental structures released over the last fifteen years has represented a further stimulus for computational investigations [4]. Thus, taking also advantage of modern hardware we may enhance our understanding of membrane protein functions and the role of specific lipid/protein ...
Proteins are highly dynamic macromolecules. To analyze their inherent flexibility, computational biologists often use molecular dynamics (MD) simulations. The quantification of protein flexibility is based on various methods such as Root Mean Square Fluctuations (RMSF) that rely on multiple MD snapshots or Normal Mode Analysis (NMA) that rely on a single structure and focus on quantifying large movements. Alternative in silico approaches assess protein motions through the protein residue network or dynamical correlations from MD simulations. An alternative yet powerful approach based on small prototypes or structural alphabets (SAs) can be used. SAs approximate conformations of protein backbones and code the local structures of proteins as one-dimensional sequences. Protein Blocks (PBs) are one of these SAs. Applying PB-based approaches to biological systems such as the DARC protein, the human αIIb β3 integrin and the KISSR1 protein highlighted the major interest of PBs in understanding local
system governing collisional processes, including N atom exchange. The related potential energy values were determined using high-level ab initio methods. The calculations were performed at a coupled-cluster with single and double and perturbative triple excitations level of theory in order to have a first full range picture of the PES. Subsequently, in order to accurately describe the stretching of the bonds of the two interacting N2 molecules by releasing the constraints of being considered as rigid rotors, for the same molecular geometries higher level of theory multi reference calculations were performed. Out of the calculated values a 6D 4-atoms global PES was produced for use in dynamical calculations. The ab initio calculations were made possible by the combined use of High Throughput Computing and High Performance Computing techniques within the frame of a computing grid empowered molecular simulator. © 2013 Wiley Periodicals, Inc. ...
Here we address this problem by using molecular mechanics simulations to build up a detailed picture of the conformational behavior of 2-amino-1-phenylethanol, a noradrenaline analogue, in aqueous solution in both its neutral and protonated forms. For the sake of comparison, equivalent simulations are also performed on the gas-phase molecules and gas-phase hydrated clusters. These calculations reveal the important role that water has to play in determining the conformational preferences and dynamic behavior of the molecules. Water molecules are found to bridge between the various functional groups within the molecule, significantly affecting their relative stabilities in comparison to the gas-phase values. The reorganization of these solvation structures also provides a mechanism for conformational interconversion. The role of the solvent in mediating interactions between the various functional groups within the molecule suggests that in noradrenaline the catechol groups will be able to ...
Traditional transcription factor binding site analyses focus solely on the nucleotide composition of site despite the fact that more recent studies have shown transcription factors to rely on the DNA structural features within and surrounding their binding sites. In this study a metric of intrinsic DNA flexibility referred to as the TRX scale is used to assess the structural features within functionally annotated binding sites and their up- and downstream flanking regions based on their Shannon information content (IC). Two methods of sequence alignment, center and a novel delta TRX based multiple sequence alignment, are compared. The results show that at least 95% of all up- and downstream flanking regions contained more IC in their structural signature as defined by the TRX scale. Between 23% and 35% (excluding and including bridging phosphate bonds, respectively) of flanking regions also showed significant differences between the sets of confirmed and non-confirmed matches. However, few to no
The Computational Molecular Design Group aims to simulate biomolecular interactions and to design effective molecular regulators using large-scale computer simulations. X-ray crystallography and NMR studies provide a large number of 3D structures of biomolecules, and advances in molecular detection technologies have greatly improved our understandings of intracellular molecular behaviors. To connect molecular behavior with molecular structure and to predict molecular functions, however, require large scale, atomic level molecular simulations. We are therefore focusing on molecular dynamics (MD) and quantum chemistry simulations to study this relationship in large biomolecules. Through collaboration with groups inside and outside QBiC, we are designing novel compounds for various target biomolecules by utilizing our computational techniques. Furthermore, by developing exclusive high-performance computers, we aim to achieve unprecedented long-term MD simulations.. ...
In 2005, Goodman and co-workers introduced the ROBIA (Reaction Outcome By Informatics Analysis) program for predicting the possible products of organic reactions and assessing the kinetic and/or thermodynamic feasibility of product formation. This program combines a series of rules based on typical reactivity patterns of certain organic functional groups with molecular mechanics and/or quantum chemical energy calculations on predicted products and/or transition state structures for possible reactions. Using this program, Goodman and co-workers predicted that (-)-dolabriferol might be formed - both biosynthetically and possibly synthetically - by a retro-Claisen reaction of a polyketide-derived precursor, i.e., they predicted that dolabriferol would likely be one of the major thermodynamic products of such a reaction. Now, Goodman and co-workers describe in ACIE a laboratory synthesis of (-)-dolabriferol that involves just such a (biomimetic) reaction (of a suitably protected precursor). This ...
We compare the geometric and physical chemical properties of interfaces involved in specific and non-specific protein-protein interactions in crystal structures reported in the Protein Data Bank. Specific interactions are illustrated by 70 protein-protein complexes and by subunit contacts in 122 homodimeric proteins; non-specific interactions, by 188 pairs of monomeric proteins making crystal packing contacts selected to bury more than 800 Å2 of protein surface. A majority of these pairs have two-fold symmetry and form crystal dimers that cannot be distinguished from real dimers on the basis of the interface size or symmetry. Their chemical and amino acid compositions resemble the protein solvent accessible surface, they are less hydrophobic than in homodimers and contain much fewer fully buried atoms. We develop a residue propensity score to assess preferences for the different types of interfaces, and we derive indexes to evaluate the atomic packing, which is less compact at non-specific than ...
Solute effects arise from PREFERENTIAL INTERACTIONS (Timasheff): Solute and water compete for the biopolymer surface Preferential Accumulation of Solute: Solute-Biopolymer interactions more favorable than interactions of both species with water Local concentration of solute higher than bulk Preferential Exclusion of Solute (Preferential Hydration) Local concentration of solute lower than bulk To describe solute distribution: Schellman 1:1 solute: water competitive binding model Our solute partitioning model; partition coefficient K p K p = m 3 loc /m 3 bulk If K p > 1, solute is accumulated; if K p < 1, solute is excluded
Lets look at folding in another way: You might guess a protein would fold to lowest free energy conformation. Problem: is there time? (Levinthals Paradox, formulated by Cyrus Levinthal in 1968) Stryer calculation (very conservative): Assume 100 aa residue protein with 3 possible conformations/residue; then get 3100or 5 x 1047 possible conformations. If search at a rate of one structure/10-13sec then get (5 x 1047)(10-13)= 5 x 1034 sec or 1.6 x 1027 years to search (and thus to fold protein). This is greater than the age of our Universe (13.7 x 109 yrs). [Rawn calculation (perhaps more realistic): same but assume 10 conformations, then get 1087sec or 3 x 1080 yrs!]. Obviously from these calculations not searching all possible conformations (or we have the process wrong!), so cannot say protein achieves the lowest global free energy, but rather a local free energy minima. (Like a valley in mountain range: a local energy minima, but not lowest [Marianas trench].) [sketch - note represents ...
The analysis software contains the unique feature whereby it can detect, quantify and annotate the various modes of atomic interactions, without the need of using pictorial or diagrammatic illustrations. This is achieved by making use of the DL_F Notation, implemented within the DL_FIELD program. From such, the DL_ANALYSER Notation for Atomic Interactions, DANAI, has been implemented. It is a natural expression system to annotate detailed, localised atomic interactions. For more details, please refer to the following reference:. C.W. Yong and I.T. Todorov, Molecules (2018), 23, 36 (doi:10.3390/molecules23010036). DL_ANALYSER is supplied to individuals under an academic licence, which is free to academic scientists pursuing scientific research of a non-commercial nature. Please see the web page Registering for the DL_ANALYSER Package for instructions. Commercial organisations interested in acquiring the package should approach Dr. C. W. Yong at Daresbury Laboratory in the first instance. ...
A series of pyrazolo[1,5-a] pyrimidines was used as a molecular model in order to understand the crystal packing of compounds with weak electrostatic intermolecular interactions. Additionally, the relationship between the energetic content of intermolecular interactions, the contact surfaces of molecules, and the thermodynamic properties of the crystal was established. The approach, which is based on a supramolecular cluster, shows that for compounds with weak electrostatic intermolecular interactions, the energetic content of the interactions is associated with a large contact surface. The crystal packing of the studied compounds is mainly governed by interactions that involve high interaction energy over a large contact surface. These results show that pi center dot center dot center dot pi interaction may be as responsible as other strong interactions for driving the crystal packing of compounds with weak electrostatic intermolecular interactions. Furthermore, the correlation between ...
Constrained modelling is well suited for determining antibody solution structures and evaluating their flexibility. Monomeric antibodies are composed of two Fab and one Fc fragments joined by two linker peptides called the hinges (Janeway et al. 2005). The hinge conformation comprises the main variable in scattering modelling. The hinge conformation is central to antibody structure and function in all five human antibody classes (IgG, IgA, IgM, IgE and IgD), in which it is the most diverse structural element (figure 4). It can be very short (IgG, IgA) or very long with 64 residues (IgD), or the linker is replaced by an extra pair of domains (IgE, IgM). Very few crystal structures for intact antibodies are known, and only for the IgG class. These crystal structures are obtained using non-physiological buffers in high salt as precipitant, and report a single snapshot view of the two hinge conformations in a single symmetric or asymmetric structure that is frozen by the intermolecular contacts ...
The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3(10)-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C-1), modeled from experimental constraints. We show that conformations within 3 angstrom of the X-ray structure are obtained in simulations starting from the C-1 model, and directly observe the previously suggested sliding 3(10)-helix region in S4. Through systematic free ...
Specific binding between proteins plays a crucial role in molecular functions and biological processes. Protein binding interfaces and their atomic contacts are typically defined by simple criteria, such as distance-based definitions that only use some threshold of spatial distance in previous studies. These definitions neglect the nearby atomic organization of contact atoms, and thus detect predominant contacts which are interrupted by other atoms. It is questionable whether such kinds of interrupted contacts are as important as other contacts in protein binding. To tackle this challenge, we propose a new definition called beta (β) atomic contacts. Our definition, founded on the β-skeletons in computational geometry, requires that there is no other atom in the contact spheres defined by two contact atoms; this sphere is similar to the van der Waals spheres of atoms. The statistical analysis on a large dataset shows that β contacts are only a small fraction of conventional distance-based contacts. To
mdrun_mpi is the main computational chemistry engine within GROMACS. Obviously, it performs Molecular Dynamics simulations, but it can also perform Stochastic Dynamics, Energy Minimization, test particle insertion or (re)calculation of energies. Normal mode analysis is another option. In this case mdrun builds a Hessian matrix from single conformation. For usual Normal Modes-like calculations, make sure that the structure provided is properly energy-minimized. The generated matrix can be diagonalized by gmx nmeig. The mdrun program reads the run input file (-s) and distributes the topology over ranks if needed. mdrun produces at least four output files. A single log file (-g) is written. The trajectory file (-o), contains coordinates, velocities and optionally forces. The structure file (-c) contains the coordinates and velocities of the last step. The energy file (-e) contains energies, the temperature, pressure, etc, a lot of these things are also printed in the log file. Optionally ...
The pneumococcal serine rich repeat protein (PsrP) is displayed on the surface of Streptococcus pneumoniae with a suggested role in colonization in the human upper respiratory tract. Full-length PsrP is a 4000 residue-long multi-domain protein comprising a positively charged functional binding region (BR) domain for interaction with keratin and extracellular DNA during pneumococcal adhesion and biofilm formation, respectively. The previously determined crystal structure of the BR domain revealed a flat compressed barrel comprising two sides with an extended beta-sheet on one side, and another beta-sheet that is distorted by loops and beta-turns on the other side. Crystallographic B-factors indicated a relatively high mobility of loop regions that were hypothesized to be important for binding. Furthermore, the crystal structure revealed an inter-molecular beta-sheet formed between edge strands of two symmetry-related molecules, which could promote bacterial aggregation during biofilm formation. ...
Extended Hückel theory and the method of perturbative configuration interaction using localized orbitals (PCILO) predict strikingly different results for the conformation of histamine cations. Extend Hückel theory predicts that both mono- and dications should exist as mixtures of trans and gauche forms, as observed with NMR studies in solution, whereas PCILO predicts a strong preference of the monocation for the gauche form and of the dication for the trans form, as shown by X-ray crystallography. In order to resolve this dilemma, nonempirical ab initio computations have been performed for the two species. They confirm the results of the PCILO calculations and indicate that the intrinsic conformational preferences of the isolated molecule correspond closely to the crystal structure data. In order to elucidate the situation prevailing in solution, the principal hydration sites of the histamine cations have been determined by calculations ab initio, and new conformational energy maps have been ...
All living systems contain proteins whose job is to move ions across a lipid membrane. Even viruses encode ion transport proteins, which they need to complete their lifecycle and release themselves from infected cells. Such proteins, called viroporins, usually consist of small subunits of one or two helices that can self-assemble in a lipid bilayer into a pore-like structure. Although in some cases, the resulting structures resemble the well-ordered, selective ion channels in higher organisms, often they take on a more disordered character, forming pores with variable numbers of subunits, which adapt their structure and behavior to the environment in which they find themselves. This inherent flexibility and disorder makes it very difficult to produce high-resolution crystal structures of viroporins, which is unfortunate, since they could offer attractive drug targets for new antiviral therapies. Computational modelling and molecular dynamics simulations can help fill in the gaps in our ...
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NMR experiments provide detailed structural information about biological macromolecules in solution. However, the amount of information obtained is usually much less than the number of degrees of freedom of the macromolecule. Moreover, the relationships between experimental observables and structural information, such as interatomic distances or dihedral angle values, may be multiple-valued and may rely on empirical parameters and approximations. The extraction of structural information from experimental data is further complicated by the time- and ensemble-averaged nature of NMR observables. Combining NMR data with molecular dynamics simulations can elucidate and alleviate some of these problems, as well as allow inconsistencies in the NMR data to be identified. Here, we use a number of examples from our work to highlight the power of molecular dynamics simulations in providing a structural interpretation of solution NMR data.
Absorption with aqueous amine solvents is at present the most viable technology for CO2 capture. While this is a proven technology, efforts are ongoing to improve it in order to make it a more attractive technology for large scale use to reduce CO2 emissions. Finding solvents with better properties is one approach to improving the technology.. In this thesis methods in computational chemistry are used to improve the understanding of the chemistry of CO2 absorption in amine-water systems. The work is also intended to provide models that can be used to predict the performance of new solvents. Such predictive models are intended to facilitate the screening for new solvents.. The main focus of the computational chemistry work has been to model solvent effects. Most of the work has been based on use of quantum mechanical calculations to determine gas phase properties and different models to determine the solvation energy. Most of the solvation energy calculations have been based on molecular ...
Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on a series of substituted 1,4-dihydroindeno[1,2-c]pyrazoles inhibitors, using molecular docking and comparative molecular field analysis (CoMFA). The docking results from GOLD 3.0.1 provide a reliable conformational alignment scheme for the 3D-QSAR model. Based on the docking conformations and alignments, highly predictive CoMFA model was built with cross-validated q 2 value of 0.534 and non-cross-validated partial least-squares analysis with the optimum components of six showed a conventional r 2 value of 0.911. The predictive ability of this model was validated by the testing set with a conventional r 2 value of 0.812. Based on the docking and CoMFA, we have identified some key features of the 1,4-dihydroindeno[1,2-c]pyrazoles derivatives that are responsible for checkpoint kinase 1 inhibitory activity. The analyses may be used to design more potent 1,4-dihydroindeno[1,2-c]pyrazoles derivatives and ...
Fields of Application. The term theoretical chemistry may be defined as a mathematical description of chemistry, whereas computational chemistry is usually used when a mathematical method is sufficiently well developed that it can be automated for implementation on a computer. In theoretical chemistry, chemists, physicists and mathematicians develop algorithms and computer programs to predict atomic and molecular properties and reaction paths for chemical reactions. Computational chemists, in contrast, may simply apply existing computer programs and methodologies to specific chemical questions.. There are two different aspects to computational chemistry:. ...
Computational chemistry is a powerful tool for understanding real-world chemical problems. The gap between experiment and computational models is growing ever smaller. Calculated results for isolated molecules are becoming more relevant and reliable calculations for larger and larger molecular systems are becoming more accessible.. A computational study of enantioselective spiroacetalization catalyzed by phosphoric acids carried out by researchers at the Universidad de Salamanca and Oxford University effectively demonstrates the ability of advanced computational methods to elucidate key and often subtle factors that lead to different reaction outcomes.. The study uses a hybrid quantum mechanics (QM)/molecular mechanics (MM) method which makes computational simulations of large systems feasible by combining an accurate quantum mechanical description of the interesting part of the system (i.e. the catalyst active site) with the computational efficiency of molecular mechanics applied to the ...
Abstract. The accurate and exhaustive description of the conformational ensemble sampled by small molecules in solution, possibly at different physiological conditions, is of primary interest in many fields of medicinal chemistry and computational biology. Recently, we have built an on-line database of compounds with antimicrobial properties, where we provide all-atom force-field parameters and a set of molecular properties, including representative structures extracted from cluster analysis over μs-long molecular dynamics (MD) trajectories. In the present work, we used a medium-sized antibiotic from our sample, namely ampicillin, to assess the quality of the conformational ensemble. To this aim, we compared the conformational landscape extracted from previous unbiased MD simulations to those obtained by means of Replica Exchange MD (REMD) and those originating from three freely-available conformer generation tools widely adopted in computer-aided drug-design. In addition, for different ...
The human APOBEC3G protein (A3G) is a single-stranded DNA deaminase that inhibits the replication of retrotransposons and retroviruses, including HIV-1. Atomic details of A3Gs catalytic mechanism have started to emerge, as the structure of its catalytic domain (A3Gctd) has been revealed by NMR and X-ray crystallography. The NMR and crystal structures are similar overall; however, differences are apparent for β2 strand (β2) and loops close to the catalytic site. To add some insight into these differences and to better characterize A3Gctd dynamics, we calculated its free energy profile by using the Generalized-Born surface area (GBSA) method accompanied with a molecular dynamics simulation. The GBSA method yielded an enthalpy term for A3Gctds free energy, and we developed a new method that takes into account the distribution of the proteins dihedral angles to calculate its entropy term. The structure solved by NMR was found to have a lower energy than that of the crystal structure, suggesting that
The major challenge of ab initio protein structure predictions is the huge conformational space populated by large proteins which has to be sampled in order to find the native structure. Due to the size of the conformational space, the probability of sampling from the vicinity of the native conformation is low. But is it really necessary to consider all possible conformations while searching? Despite having diverse shapes and functions, proteins only populate a tiny part of the space of possible conformations. Our goal is to leverage our knowledge about these populated topologies to guide the search. We strongly believe that using this information during sampling will alleviate many of the problems arising from the size of the conformational space. This in turn should allow us to predict many proteins which are traditionally unsolved by ab initio. Contact: Mahmoud Mabrouk ...
Computational chemistry offers many avenues to investigate physical phenomena at the molecular level which is usually not totally captured by experiments. Its applications on biological problems present a whole new perspective to living organisms at a micro scale. Folding mechanisms of proteins into their functional forms, assembly formation mechanisms of multiple proteins, signal transduction pathways through a series of proteins and lipids, interactions of proteins and nucleic acids, catalysis pathways of enzymes, and binding principles of small molecules to enzymes belong to a long list of areas to be explored with computational chemistry to make sense of observations made at macroscopic scale.This dissertation features discussions pertaining protein structure, dynamics, and ligand binding. Quantum mechanics and molecular dynamics are employed to gain insights into sample problems in these areas. The first chapter introduces how computational chemistry might aid in the understanding of ...
An implementation of Ewald summation for use in mixed quantum mechanics/molecular mechanics (QM/MM) calculations is presented, which builds upon previous work by others that was limited to semi-empirical electronic structure for the QM region. Unlike previous work, our implementation describes the wave functions periodic images using ChElPG atomic charges, which are determined by fitting to the QM electrostatic potential evaluated on a real-space grid. This implementation is stable even for large Gaussian basis sets with diffuse exponents, and is thus appropriate when the QM region is described by a correlated wave function. Derivatives of the ChElPG charges with respect to the QM density matrix are a potentially serious bottleneck in this approach, so we introduce a ChElPG algorithm based on atom-centered Lebedev grids. The ChElPG charges thus obtained exhibit good rotational invariance even for sparse grids, enabling significant cost savings. Detailed analysis of the optimal choice of ...
This thesis presents and uses the techniques of computational chemistry to explore two different processes induced in human skin by ultraviolet light. The first is the transformation of urocanic acid into a immunosuppressing agent, and the other is the enzymatic action of the 8-oxoguanine glycosylase enzyme. The photochemistry of urocanic acid is investigated by time-dependent density functional theory. Vertical absorption spectra of the molecule in different forms and environments is assigned and candidate states for the photochemistry at different wavelengths are identified. Molecular dynamics simulations of urocanic acid in gas phase and aqueous solution reveals considerable flexibility under experimental conditions, particularly for for the cis isomer where competition between intra- and inter-molecular interactions increases flexibility. A model to explain the observed gas phase photochemistry of urocanic acid is developed and it is shown that a reinterpretation in terms of a mixture ...
The protein structure prediction (PSP) problem is concerned with the prediction of native tertiary structure of a protein given its sequence of amino acids. Ab-initio approach to PSP problem assumes that native conformation of protein corresponds to the global minimum free energy state. The potential energy used to evaluate the conformation of a protein is based on different interaction energies. In the present work, potential energy function Chemistry at HARvard Macromolecular Mechanics (CHARMM) has been used to qualitatively assess the conformations. Backbone and side-chain torsion angles are used to represent each conformation. In the present thesis, we have used Bacterial Foraging Optimization Algorithm as a search procedure for exploring the conformational space of the PSP problem. Results obtained indicate that this is another promising way of finding the stable structure of protein ...
A series of crystal structures of trypsin, containing either an autoproteolytic cleaved peptide fragment or a covalently bound inhibitor, were determined at atomic and ultra-high resolution and subjected to ab initio quantum chemical calculations and multipole refinement. Quantum chemical calculations reproduced the observed active site crystal structure with severe deviations from standard stereochemistry and indicated the protonation state of the catalytic residues. Multipole refinement directly revealed the charge distribution in the active site and proved the validity of the ab initio calculations. The combined results confirmed the catalytic function of the active site residues and the two water molecules acting as the nucleophile and the proton donor. The crystal structures represent snapshots from the reaction pathway, close to a tetrahedral intermediate. The de-acylation of trypsin then occurs in true SN2 fashion. Trypsin revisited: crystallography AT (SUB) atomic resolution and quantum ...
Author(s): Tang, Zhiye; Chen, Si-Han; Chang, Chia-En A | Abstract: This study presents a novel computational approach to study molecular recognition and binding kinetics for drug-like compounds dissociating from a flexible protein system. The intermediates and their free energy profile during ligand association and dissociation processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. The method applied the milestoning theory to extract kinetics and thermodynamics information from running short classical molecular dynamics (MD) simulations for frames from a given dissociation path. High-dimensional ligand-protein motions (3N-6 degrees of freedom) during ligand dissociation were reduced by use of principal component modes for assigning more than 100 milestones, and classical MD runs were allowed to travel multiple milestones to efficiently obtain ensemble distribution of initial structures for MD simulations and estimate the transition time and rate
Protein model refinement is the last step applied to improve the quality of a predicted protein model. Currently, the most successful refinement methods rely on extensive conformational sampling and thus take hours or days to refine even a single protein model. Here, we propose a fast and effective model refinement method that applies graph neural networks (GNNs) to predict a refined inter-atom distance probability distribution from an initial model and then rebuilds three-dimensional models from the predicted distance distribution. Tested on the Critical Assessment of Structure Prediction refinement targets, our method has an accuracy that is comparable to those of two leading human groups (FEIG and BAKER), but runs substantially faster. Our method may refine one protein model within ~11 min on one CPU, whereas BAKER needs ~30 h on 60 CPUs and FEIG needs ~16 h on one GPU. Finally, our study shows that GNN outperforms ResNet (convolutional residual neural networks) for model refinement when very limited
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In most of homeodomain-DNA complexes, glutamine or lysine is present at 50th position and interacts with 5th and 6th nucleotide of core recognition region. Molecular dynamics simulations of Msx-1-DNA complex (Q50-TG) and its variant complexes, that is specific (Q50K-CC), nonspecific (Q50-CC) having mutation in DNA and (Q50K-TG) in protein, have been carried out. Analysis of protein-DNA interactions and structure of DNA in specific and nonspecific complexes show that amino acid residues use sequence-dependent shape of DNA to interact. The binding free energies of all four complexes were analysed to define role of amino acid residue at 50th position in terms of binding strength considering the variation in DNA on stability of protein-DNA complexes. The order of stability of protein-DNA complexes shows that specific complexes are more stable than nonspecific ones. Decomposition analysis shows that N-terminal amino acid residues have been found to contribute maximally in binding free energy of ...
Calculations have been performed on the entire Fe(Schiff base) · cdHO system using the QM/MM ONIOM (DFT : AMBER) method implemented in Gaussian 09 [29]. The charges and protonation states of all titrable amino acids were automatically assigned using the interface provided by the UCSF Chimera package [30] with the exception of the iron-chelating histidine His20, which was manually set to be consistent with the coordination rules of the metal. Visual inspection was subsequently performed. The total charge of the system is −8 or −7 depending on the oxidation state of the iron. It can be divided by −10 for the isolated protein and +2 or +3 for the inorganic complex. The QM part in the QM/MM partition has a charge +1 in the Fe(II) species and +2 for the Fe(III) ones.. One of the main objectives of this work is to determine whether the experimental structure corresponds to a plausible electronic structure of the metal centre in a resting state configuration or not. Thus, we are interested in ...
The IntFOLD-TS method was developed according to the guiding principle that the model quality assessment (QA) would be the most critical stage for our template-based modeling pipeline. Thus, the IntFOLD-TS method firstly generates numerous alternate models, using in-house versions of several different sequence-structure alignment methods, which are then ranked in terms of global quality using our top performing QA method-ModFOLDclust2. In addition to the predicted global quality scores, the predictions of local errors are also provided in the resulting coordinate files, using scores that represent the predicted deviation of each residue in the model from the equivalent residue in the native structure. The IntFOLD-TS method was found to generate high quality 3D models for many of the CASP9 targets, whilst also providing highly accurate predictions of their per-residue errors. This important information may help to make the 3D models that are produced by the IntFOLD-TS method more useful for ...
Li, Yuan and Hu, Ning and Yamamoto, Go and Wang, Zhongchang and Hashida, Toshiyuki and Asanuma, Hiroshi and Dong, Chensong and Okabe, Tomonaga and Arai, Masahiro and Fukunaga, Hisao. 2010. Molecular mechanics simulation of the sliding behavior between nested walls in a multi-walled carbon nanotube. Carbon. 48 (10): pp. 2934-2940 ...
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Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) have remarkably similar chemical structures, but despite this, they play significantly different roles in modern biology. In this article, we explore the possible conformations of DNA and RNA hairpins to better understand the fundamental differences in structur Complex molecular systems: supramolecules, biomolecules and interfaces
BACKGROUND: Protein fold recognition usually relies on a statistical model of each fold; each model is constructed from an ensemble of natural sequences belonging to that fold. A complementary strategy may be to employ sequence ensembles produced by computational protein design. Designed sequences can be more diverse than natural sequences, possibly avoiding some limitations of experimental databases. METHODOLOGY/PRINCIPAL FINDINGS: WE EXPLORE THIS STRATEGY FOR FOUR SCOP FAMILIES: Small Kunitz-type inhibitors (SKIs), Interleukin-8 chemokines, PDZ domains, and large Caspase catalytic subunits, represented by 43 structures. An automated procedure is used to redesign the 43 proteins. We use the experimental backbones as fixed templates in the folded state and a molecular mechanics model to compute the interaction energies between sidechain and backbone groups. Calculations are done with the [email protected] volunteer computing platform. A heuristic algorithm is used to scan the sequence and conformational
Research outputs, collaborations and relationships for Laboratory of Computational Chemistry and Drug Design, PKU Shenzhen published between 1 December 2018 - 30 November 2019 as tracked by the Nature Index.
As a member of the wwPDB, the RCSB PDB curates and annotates PDB data according to agreed upon standards. The RCSB PDB also provides a variety of tools and resources. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists.
How is Molecular description of Aggregation, Denaturation, Gelation And Surface activity of whey proteins abbreviated? MADGELAS stands for Molecular description of Aggregation, Denaturation, Gelation And Surface activity of whey proteins. MADGELAS is defined as Molecular description of Aggregation, Denaturation, Gelation And Surface activity of whey proteins very frequently.
Phenolic resins are important adhesives used by the forest products industry. The phenolic compounds in these resins are derived primarily from petrochemical sources. Alternate sources of phenolic compounds include tannins, lignins, biomass pyrolysis products, and coal gasification products. Because of variations in their chemical structures, the reactivities of these phenolic compounds with formaldehyde vary in quite subtle ways. A method is needed for predicting the reactivity of phenolic compounds with formaldehyde in order to allow researchers to efficiently choose those compounds that might make the best candidates for new adhesive systems prior to conducting extensive laboratory trials. Computational chemistry has been used to study the relationship between the reactivity of a number of phenolic compounds with formaldehyde in an aqueous, alkaline system, and charges calculated for reactive sites on the aromatic ring of the phenolic compound. Atomic-charges for each phenolic compound were ...
Mature HIV-1 particles contain conical-shaped capsids that enclose the viral RNA genome and perform essential functions in the virus life cycle. Previous structural analysis of two- and three-dimensional arrays of the capsid protein (CA) hexamer revealed three interfaces. Here, we present a cryoEM study of a tubular assembly of CA and a high-resolution NMR structure of the CA C-terminal domain (CTD) dimer. In the solution dimer structure, the monomers exhibit different relative orientations compared to previous X-ray structures. The solution structure fits well into the EM density map, suggesting that the dimer interface is retained in the assembled CA. We also identified a CTD-CTD interface at the local three-fold axis in the cryoEM map and confirmed its functional importance by mutagenesis. In the tubular assembly, CA intermolecular interfaces vary slightly, accommodating the asymmetry present in tubes. This provides the necessary plasticity to allow for controlled virus capsid dis/assembly.
Although some scientists, such as many physicists, may prefer a commandline approach to submitting computational jobs, a majority of scientists want to be shielded from the commandline. A popular approach is to build portals; user community web sites that allow job submissions from the convenience of a web browser. The development of such portals typically takes many months as the developer has to learn how to integrate the various components: a portal system such as GridSphere, a job submission architecture such as Globus, a security system such as the Java CoG Kit, a system for staging input and output files, and so on. In this project, you will design and implement a job submission portal for computational chemistry (http://www.eastchem.ac.uk/). They already have clusters in place and also have access to the Edinburgh Compute Data Facility (http://www.ecdf.ed.ac.uk/). They use grid certificates and rely on Globus for job submissions.. You will _not_ use the conventional approach of ...
Basic molecular structural principles of biological materials. Molecular structures of various materials of biological origin, including collagen, silk, bone, protein adhesives, GFP, self-assembling peptides. Molecular design of new biological materials for nanotechnology, biocomputing and regenerative medicine. Graduate students are expected to complete additional coursework. Description from course home page: This course, intended for both graduate and upper level undergraduate students, will focus on understanding of the basic molecular structural principles of biological materials. It will address the molecular structures of various materials of biological origin, such as several types of collagen, silk, spider silk, wool, hair, bones, shells, protein adhesives, GFP, and self-assembling peptides. It will also address molecular design of new biological materials applying the molecular structural principles. The long-term goal of this course is to teach molecular design of new biological ...
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Green fluorescent protein (GFP) is a luminescent protein with a central chromophore and is used in biological imaging. By modifying the chromophore itself or the protein environment, the photophysical properties can be fine-tuned, yet until recently this has not been well understood. However, Lars Andersen (Aarhus University) and his group have developed a laser-action spectroscopy technique to enable the chromophore to be studied in a vacuum. This has revealed that a single hydrogen bond initiated a 0.5eV shift in the absorption spectrum of the GFP chromophore and highlights the importance of understanding the biophysics of chromophores and how this can help in the development of new colour chromophores.. ...
Aspartic proteases regulate many biological processes and are prominent targets for therapeutic intervention. Structural studies have captured intermediates along the reaction pathway, including the Michaelis complex and tetrahedral intermediate. Using a Ramachandran analysis of these structures, we discovered that residues occupying the P1 and P1′ positions (which flank the scissile peptide bond) adopt the dihedral angle of an inverse γ-turn and polyproline type-II helix, respectively. Computational analyses reveal that the polyproline type-II helix engenders an n→π∗ interaction in which the oxygen of the scissile peptide bond is the donor. This interaction stabilizes the negative charge that develops in the tetrahedral intermediate, much like the oxyanion hole of serine proteases. The inverse γ-turn serves to twist the scissile peptide bond, vacating the carbonyl π∗ orbital and facilitating its hydration. These previously unappreciated interactions entail a form of ...
TY - JOUR. T1 - Spectral properties of thermal fluctuations on simple liquid surfaces below shot-noise levels. AU - Aoki, Kenichiro. AU - Mitsui, Takahisa. PY - 2012/7/18. Y1 - 2012/7/18. N2 - We study the spectral properties of thermal fluctuations on simple liquid surfaces, sometimes called ripplons. Analytical properties of the spectral function are investigated and are shown to be composed of regions with simple analytic behavior with respect to the frequency or the wave number. The derived expressions are compared to spectral measurements performed orders of magnitude below shot-noise levels, which is achieved using a novel noise reduction method. The agreement between the theory of thermal surface fluctuations and the experiment is found to be excellent, elucidating the spectral properties of the surface fluctuations. The measurement method requires relatively only a small sample both spatially (few μm) and temporally (∼20s). The method also requires relatively weak light power ...
TY - JOUR. T1 - Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo. AU - Woods, Chanin T.. AU - Lackey, Lela. AU - Williams, Benfeard. AU - Dokholyan, Nikolay V.. AU - Gotz, David. AU - Laederach, Alain. N1 - Funding Information: This work was supported by the National Institutes of Health (NIH) under grant Nos. HL111527, GM101237, and HG008133 to A.L., grant Nos. R01 GM123238-01, 1R01GM123247, and R01 GM064803-12 to N.V.D., and grant No. 3R01GM080742-08S1 to B.W. L.L. was supported by an American Cancer Society ? Lee National Denim Day Postdoctoral Fellowship, grant No. PF-15-133-01-RMC. Publisher Copyright: © 2017 Biophysical Society Copyright: Copyright 2017 Elsevier B.V., All rights reserved.. PY - 2017/7/25. Y1 - 2017/7/25. N2 - When a ribonucleic acid (RNA) molecule folds, it often does not adopt a single, well-defined conformation. The folding energy landscape of an RNA is highly dependent on its nucleotide sequence and molecular environment. Cellular ...
Within the Born-Oppenheimer picture of the electronic Schrödinger equation the external potential due to the nuclei influences the resulting expectation values during the self consistent field procedure. In this thesis, the optimization and the benefit of atom centered potentials for an improved description and design of molecules is studied using density functional theory (DFT). It is shown that atom centered potentials can be used to increase the accuracy of the description of molecular properties as well as to generally explore chemical space rationally for structures which exhibit desired properties. The wide range of possible applications is illustrated by addressing several issues. First, an automated procedure is proposed for the design of optimal link pseudopotentials for quantum mechanics/molecular mechanics calculations. Secondly, it is shown how to tune variationally atom centered potentials within density functional perturbation theory in order to minimize the deviation in electron density
This paper proposes a new approach to construct high quality space-filling sample designs. First, we propose a novel technique to quantify the space-filling property and optimally trade-off uniformity and randomness in sample designs in arbitrary dimensions. Second, we connect the proposed metric (defined in the spatial domain) to the quality metric of the design performance (defined in the spectral domain). This connection serves as an analytic framework for evaluating the qualitative properties of space-filling designs in general. Using the theoretical insights provided by this spatial-spectral analysis, we derive the notion of optimal space-filling designs, which we refer to as space-filling spectral designs. Third, we propose an efficient estimator to evaluate the space-filling properties of sample designs in arbitrary dimensions and use it to develop an optimization framework for generating high quality space-filling designs. Finally, we carry out a detailed performance comparison on two ...
In the study reported in this paper, we characterized anisotropic van der Waals interactions programmed into microparticles via control of internal LC ordering by quantifying kinetically controlled colloid adsorption over the surfaces of the LC microparticles. Our experiments and supporting calculations revealed that spatial variation of the van der Waals interactions across the surfaces of the LC microparticles was as large as 20 kBT, a magnitude that is sufficiently large to be useful in engineering the bottom-up assembly of soft materials (18). We note that the LC microparticles used in our experiments were prepared by polymerization of RM257. The polymer network formed by the RM257 prevented lateral motion of probe colloids that adsorbed to the surfaces of the LC microparticles. In contrast, a number of past studies have reported adsorption of colloids onto the surfaces of LC microdroplets with mobile interfaces (23, 30). When the interfaces of the LC microdroplets are mobile, adsorbed ...
Zinc-fingers play crucial roles in regulating gene expression and mediating protein-protein interactions. In this article, two different proteins (Sp1f2 and FSD-1) are investigated using the Gaussian network model and anisotropy elastic network model. By using these simple coarse-grained methods, we analyze the structural stabilization and establish the unfolding pathway of the two different proteins, in good agreement with related experimental and molecular dynamics simulation data. From the analysis, it is also found that the folding process of the zinc-finger motif is predominated by several factors. Both the zinc ion and C-terminal loop affect the folding pathway of the zinc-finger motif. Knowledge about the stability and folding behavior of zinc-fingers may help in understanding the folding mechanisms of the zinc-finger motif and in designing new zinc-fingers. Meanwhile, these simple coarse-grained analyses can be used as a general and quick method for mechanistic studies of metalloproteins.
Protein folding is a complex process involving van der Waals and hydrophobic interactions, electrostatics, and hydrogen bonding networks. One approach to understanding protein folding is to design from scratch a particular protein fold, thoroughly characterize its solution properties, and determine its three-dimensional structure. The field of de novo protein design (1, 2) has experienced some recent exciting successes in the redesign of natural proteins to incorporate novel, functional metal-binding sites (3, 4). Also, the redesign of proteins patterned after the sequence or three-dimensional structural motifs such as the zinc finger (5-8), coiled coils (9), or other small protein domains (10, 11) has progressed quite significantly. Unnatural right-handed coiled coils have been successfully designed (12), and small, marginally stable models for protein secondary (13, 14) and supersecondary structures, including helix-loop-helix (15, 16) and three-stranded β-hairpin motifs (17-20), have been ...
TY - JOUR. T1 - Prediction of the receptor conformation for iGluR2 agonist binding. T2 - QM/MM docking to an extensive conformational ensemble generated using normal mode analysis. AU - Sander, Tommy. AU - Liljefors, Tommy. AU - Balle, Thomas. N1 - Keywords: Protein flexibility, molecular docking, normal mode analysis, elastic network model, ensemble generation, iGluR2 receptor, domain closure. PY - 2008. Y1 - 2008. KW - Former Faculty of Pharmaceutical Sciences. U2 - 10.1016/j.jmgm.2007.11.006. DO - 10.1016/j.jmgm.2007.11.006. M3 - Journal article. VL - 26. SP - 1259. EP - 1268. JO - Journal of Molecular Graphics and Modelling. JF - Journal of Molecular Graphics and Modelling. SN - 1093-3263. IS - 8. ER - ...
We introduce a new type of knowledge-based potentials for protein structure prediction, called evolutionary potentials, which are derived using a single experimental protein structure and all three-dimensional models of its homologous sequences. The new potentials have been benchmarked against other knowledge-based potentials, resulting in a significant increase in accuracy for model assessment. In contrast to standard knowledge-based potentials, we propose that evolutionary potentials capture key determinants of thermodynamic stability and specific sequence constraints required for fast folding.
Electrostatic interactions between ligands and their receptors are important factors for molecular recognition. Assessing the ligand-receptor electrostatic complementarity provide valuable information for molecular design. In this hands-on workshop we will focus on using Flare™, Cressets structure-based design application to design ligands that are electrostatically complementary to the protein active site. You will learn how to visualize ligand-protein interactions; design new molecules in the context of the active site; easily dock new molecule designs to a protein active site; and assess the electrostatic complementarity between ligands and protein.
The three-dimensional structure of a ternary complex of the purine repressor, PurR, bound to both its corepressor, hypoxanthine, and the 16-base pair purF operator site has been solved at 2.7 A resolution by x-ray crystallography. The bipartite structure of PurR consists of an amino-terminal DNA-binding domain and a larger carboxyl-terminal corepressor binding and dimerization domain that is similar to that of the bacterial periplasmic binding proteins. The DNA-binding domain contains a helix-turn-helix motif that makes base-specific contacts in the major groove of the DNA. Base contacts are also made by residues of symmetry-related alpha helices, the hinge helices, which bind deeply in the minor groove. Critical to hinge helix-minor groove binding is the intercalation of the side chains of Leu54 and its symmetry-related mate, Leu54, into the central CpG-base pair step. These residues thereby act as leucine levers to pry open the minor groove and kink the purF operator by 45 degrees. ...
The potential energy surface (PES) of tyrosyl-glycyl-glycine (YGG) tripeptide in solution was explored using EDMC (Electrostatically Driven Monte Carlo) and in the gas-phase by means of ab initio quantum chemical calculations. The theoretical computational analysis revealed that this tripeptide possesses a significant molecular flexibility. A C7 backbone conformation was the most energetically preferred for the central Gly residue, using both methodologies. Some new stable conformers that have not been previously reported were identified in the gas phase as well. This study points out the interplay of backbone and side-chain contributions in determining the relative stabilities of energy minima. In addition, the peptide backbone of YGG was compared with other small peptides containing aromatic side-chains (Phe-Gly-Gly and Trp-Gly-Gly). The comparison with experimental X-ray results was also satisfactory ...