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 ...
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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... , Computational Chemistry List, Resource for Computational Chemists, molecular modeling, and associated archives
... , 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
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
... 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 ...
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. ...
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. ...
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
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 ...
The ClH⋯FH and FH⋯ClH configurations of the mixed HF/HCl dimer (where the donor⋯acceptor notation indicates the directionality of the hydrogen bond) as well as the transition state connecting the two configurations have been optimized using MP2 and CCSD(T) with correlation consistent basis sets as large as aug-cc-pV(5 + d)Z. Harmonic vibrational frequencies confirmed that both configurations correspond to minima and that the transition state has exactly one imaginary frequency. In addition, anharmonic vibrational frequencies computed with second-order vibrational perturbation theory (VPT2) are within 6 cm-1 of the available experimental values and deviate by no more than 4 cm-1 for the complexation induced HF frequency shifts ...
The accurate description of cis/trans peptide structures is of fundamental relevance for the field of protein modeling and protein structure determination. A comprehensive conformational analysis of dipeptide model Ace-GlyNMe (1) has been carried out by using a combination of theoretical calculations and experimental (H-1 and C-13 NMR and NOESY) spectroscopic measurements to assess the relevance of cis-peptide conformers. NMR measurements in dimethyl sulfoxide (DMSO) solution and calculations employing a continuum solvation model both point to the extended trans,-trans conformer C5_tt as the global minimum. The cis-peptide structures C5_ct and C5_tc, with the N-or C-terminal amide group in cis-conformation, are observed separately and located 13.0 +/- 2 kJmol(-1) higher in energy. This is in close agreement with the theoretical prediction of around 12 kJmol(-1) in DMSO. The ability of common protein force fields to reproduce the energies of the cis-amide conformers C5_ct and C5_tc in 1 is ...
This picture of the determinants of anion-cation selectivity for the CNG channels differs from that currently envisaged for the cation selectivity of K+ channels. In KcsA, the appropriate electrostatic environment for cations within the pore is considered to be predominantly (∼80%) the result of pore helix dipoles projected toward the internal cavity at the interior end of the selectivity filter (Roux and MacKinnon, 1999; Roux et al., 2000). In contrast for CNG channels, we suggest that pore helix dipoles are not critical for determining anion-cation selectivity but, as indicated above, that this is determined by the polarity of the 0′ residues. However, as discussed earlier, we do suggest that these pore helix dipoles may contribute to the outward rectification of the E0′K/R mutant CNG channels in symmetrical solutions.. It should also be noted that a recent study on the role of the pore helix dipoles in the inward rectifier (Kir2.1), in which positive charges were introduced in the K+ ...
1NC8: High-resolution solution NMR structure of the minimal active domain of the human immunodeficiency virus type-2 nucleocapsid protein.
1NC8: High-resolution solution NMR structure of the minimal active domain of the human immunodeficiency virus type-2 nucleocapsid protein.
Protein Structures via Force Field X (FFX) Protein structures are now provided on gene pages where available. These structures were modeled using Force Field X, an atomic resolution molecular modeling application. A promising source of evidence for classifying genetic variants is atomic resolution physics-based simulation techniques, which can test physical hypotheses about pathogenic mechanisms more rapidly and at a lower cost than many experimental approaches (e.g. model organisms). However, protein structural models (e.g. from X-ray crystallography, NMR, or homology modeling) required for simulation of hearing-related proteins are often based on imperfect experimental information (e.g. low-resolution diffraction) or may contain defects due to limited homology. We combine an advanced polarizable potential energy function, novel many-body optimization theory, and GPU-acceleration to locally and globally optimize all available deafness-associated protein models through the Force Field X (FFX) ...
Several novel techniques are employed for protein tertiary structure prediction, but the more successful ones are those that rely either solely or partly on template/homology based modeling of full or sub-structures. However, a critical look at the yearly
TY - JOUR. T1 - Structural insights into steroid hormone binding. AU - Valjakka, Jarkko. AU - Takkinen, Kristiina. AU - Teerinen, Tuija. AU - Söderlund, Hans. AU - Rouvinen, Juha. PY - 2002. Y1 - 2002. N2 - The monoclonal anti-testosterone antibody (3-C4F5) has a relatively high affinity (3 × 108 M −1) with an overall good specificity profile. However, the earlier characterized binding properties have shown that both the affinity and specificity of this antibody must be improved if it is intended for use in clinical immunoassays. In this paper, the crystal structures of the recombinant anti-testosterone (3-C4F5) Fab fragment have been determined in the testosterone-bound and free form at resolutions of 2.60 and 2.72 Å, respectively. The high affinity binding of the (3-C4F5) Fab is mainly determined by shape complementarity between the protein and testosterone. Only one direct hydrogen bond is formed between the hydroxyl group of the testosterone D-ring and the main-chain oxygen of Gly100JH. ...
Background: Techniques for inferring the functions of the protein by comparing their shape similarity have been receiving a lot of attention. Proteins are functional units and their shape flexibility occupies an essential role in various biological processes. Several shape descriptors have demonstrated the capability of protein shape comparison by treating them as rigid bodies. But this may give rise to an incorrect comparison of flexible protein shapes. Results: We introduce an efficient approach for comparing flexible protein shapes by adapting a local diameter (LD) descriptor. The LD descriptor, developed recently to handle skeleton based shape deformations [1], is adapted in this work to capture the invariant properties of shape deformations caused by the motion of the protein backbone. Every sampled point on the protein surface is assigned a value measuring the diameter of the 3D shape in the neighborhood of that point. The LD descriptor is built in the form of a one dimensional histogram ...
Link for Professor Gonzalez. Abstract: Over the past two decades, stunning breakthroughs in the field of structural biology have continued to produce groundbreaking high-resolution structures of large, multi-component biomolecular machines. Comparative analyses of these static structures reveals the remarkable conformational flexibility of these machines and hints at the significant structural rearrangements that evidently accompany their functional cycles. Unfortunately, the experimental observation and characterization of these conformational dynamics is severely impeded by the size and complexity of biomolecular machines, severely limiting our understanding of the contributions that dynamics make to their functions. Using a combination of molecular genetic-, biochemical-, and single-molecule biophysical approaches, my research group aims to overcome these challenges and elucidate the precise roles that the conformational dynamics of biomolecular machines play in driving and controlling their ...
The conformation-independent structural comparison tool ProSMART (Procrustes Structural Matching Alignment and Restraints Tool) is designed to allow fast but detailed comparative analysis of macromolecular structures in the presence of conformational changes. ProSMART is suited to the analysis of the structural conservation of local backbone and side chains in a wide variety of scenarios: the method is sensitive enough to allow identification of subtle dissimilarities between structures sharing high sequence homology, whilst being versatile enough to scale to the identification of surprising local similarities between more distantly related structures.. ProSMART compares local structures using n-residue backbone fragments. These constructs allow comparisons to be performed at a chosen level of structural resolution or at multiple resolutions (note that this does not refer to crystallographic resolution, but rather to the level of structural detail). In contrast with most other features (e.g. ...
Motivation:In silico methods are being widely used for identifying substrates for various kinases and deciphering cell signaling networks. However, most of the available phosphorylation site prediction methods use motifs or profiles derived from a known data set of kinase substrates and hence, their applicability is limited to only those kinase families for which experimental substrate data is available. This prompted us to develop a novel multi-scale structure-based approach which does not require training using experimental substrate data.. Results:In this work, for the first time, we have used residue-based statistical pair potentials for scoring the binding energy of various substrate peptides in complex with kinases. Extensive benchmarking on Phospho.ELM data set indicate that our method outperforms other structure-based methods and has a prediction accuracy comparable to available sequence-based methods. We also demonstrate that the rank of the true substrate can be further improved, if ...
David Sherrill, a leader in the field of computational studies of stacking interactions, from the Georgia Institute of Technology in Atlanta, US, says: What this paper seems to show is that in some cases pi-pi interactions can be enhanced by breaking the aromaticity to yield localised pi orbitals. This is a big surprise, and I think most of the community would not have expected that result, he says. It is commonly the case that when one is making some supramolecular systems, the presence of an aromatic interaction is considered the favourable recognition element, and it still is. But now, I think we can broaden our view to look at a wider variety of these recognition elements, he adds ...
one of commercially important fish species in China. Then, 3-D structure model of the mullet IL-22 was constructed by comparative modeling method using human IL-22 (1M4R) as template, and a 5 ns molecular dynamics (MD) was studied. The open reading frame (ORF) of mullet IL-22 cDNA was 555 bp, encoding 184 amino acids. The mullet IL-22 shared higher identities with the other fish IL-22 homologs and possessed a conserved IL-10 signature motif at its C-terminal. The mullet IL-22 model possessed six conserved helix structure. PROCHECK, SAVES and Molprobity server analysis confirmed that this model threaded well with human IL-22. Strikingly, analysis with CastP, cons-PPISP server suggested that the cysteines in mullet IL-22 might not be involved in the forming of disulfide bond for structural stabilization, but related to protein-protein interactions ...
It is nice that the prediction performance can be improved a lot if applied to more realistic NMR-derived ensembles. This is expected because the experimental chemical shift of a given nucleus reflects the Boltzmann-weighted average of the instantaneous chemical shifts of a large number of conformational substates that interconvert on the millisecond timescale or faster. This behavior has been discussed many times in the literature. All Ubiquitin NMR structures cited in this work are generated specifically to be a more realistic presentation of protein ensemble in solutions, except 1D3Z. 1D3Z is a traditional NMR structure model, where NMR conformer "bundle" should not be confused with a dynamic ensemble representation of the protein. In these types of NMR models, the spread of atomic positions merely provides information about the uncertainties of the atomic positions with respect to the average structure and has no direct physical meaning. The author may need to provide more comments on this ...
It is nice that the prediction performance can be improved a lot if applied to more realistic NMR-derived ensembles. This is expected because the experimental chemical shift of a given nucleus reflects the Boltzmann-weighted average of the instantaneous chemical shifts of a large number of conformational substates that interconvert on the millisecond timescale or faster. This behavior has been discussed many times in the literature. All Ubiquitin NMR structures cited in this work are generated specifically to be a more realistic presentation of protein ensemble in solutions, except 1D3Z. 1D3Z is a traditional NMR structure model, where NMR conformer "bundle" should not be confused with a dynamic ensemble representation of the protein. In these types of NMR models, the spread of atomic positions merely provides information about the uncertainties of the atomic positions with respect to the average structure and has no direct physical meaning. The author may need to provide more comments on this ...
It is nice that the prediction performance can be improved a lot if applied to more realistic NMR-derived ensembles. This is expected because the experimental chemical shift of a given nucleus reflects the Boltzmann-weighted average of the instantaneous chemical shifts of a large number of conformational substates that interconvert on the millisecond timescale or faster. This behavior has been discussed many times in the literature. All Ubiquitin NMR structures cited in this work are generated specifically to be a more realistic presentation of protein ensemble in solutions, except 1D3Z. 1D3Z is a traditional NMR structure model, where NMR conformer "bundle" should not be confused with a dynamic ensemble representation of the protein. In these types of NMR models, the spread of atomic positions merely provides information about the uncertainties of the atomic positions with respect to the average structure and has no direct physical meaning. The author may need to provide more comments on this ...
Protein NMR is the method of choice for determining protein structures at the atomic level in solution. In addition, NMR experiments allow characterization of protein dynamics at a wide range of time scales [1-7]. Dynamical studies of the past decade led to the emerging paradigm that the so-called native structure of a protein can be better viewed as a number of more or less similar conformers interconverting on different time scales. Functional interactions perturb this state by shifting the equilibrium towards active conformations that are present but are low-populated in the apo state. The most extreme examples of this kind of behavior are provided by intrinsically disordered proteins (IDPs) that adopt a plethora of diverse conformations in their free state but, at least some of them, might become fully or partially well ordered upon partner molecule binding [8, 9].. IDPs can not be described with single-conformer models but only with conformational ensembles capturing the diversity of ...
The functions of biological systems emerge from the structures of macromolecules, their conformational dynamics, and their higher order assembly. Determination of biomolecular structures and an understanding of their conformational changes and assembly properties provide great insights into biological mechanisms. Much of the research in structural biology at the Weizmann Institute is carried out in the Faculty of Chemistry, using a diverse set of cutting-edge research tools and methods. Investigators in the Structural Biology Department rely on the primary techniques for experimental structure determination, namely X-ray crystallography, NMR, and electron microscopy, but they also employ a variety of other specialized and emerging spectroscopic methods combined with creative molecular engineering to explore macromolecular structures, energetics, and dynamics. Experimental strategies are complemented by computational and theoretical approaches. Among the specific subjects of research in the ...
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Synonyms for a-helix in Free Thesaurus. Antonyms for a-helix. 15 synonyms for helix: spiral, twist, curl, loop, coil, corkscrew, gyre, curlicue, volute, spiral, coil, volute, whorl, spiral, genus Helix. What are synonyms for a-helix?
Abstract. The prediction of binding modes (BMs) occurring between a small molecule and a target protein of biological interest has become of great importance for drug development. The overwhelming diversity of needs leaves room for docking approaches addressing specific problems. A Fast docking using the CHARMM force field with EADock DSS for the Implementation of the Hungarian algorithm to account for ligand symmetry and similarity in structure-based design of drug-like molecules by a fragment-based molecular evolutionary approach. HIV-1 P24-derived peptides were examined to predict anti-HIV-1 activity among them. The efficacy of the prediction has already been validated in vitro. Our in silico experimental studies performed on the mentioned peptides, which may lead to new anti-HIV-1 peptide-mimotopic therapeutics candidates. In this research study we presented for the first time a computational approach and a combined molecular docking-based and pharmacophore-based target prediction strategy ...
Hi Andrew: andrew holway wrote: , Multi reference quantum chem. Gaussian and Molcas. Without doing a benchmark it will be quite hard to indicate which one may be faster. Barcelona is a quad core with a good memory system (relative to the Clovertown). If your problems are large enough to spill to disk for matrix elements, then it isnt likely that the CPU performance would be the dominating factor. If you have enough ram that your problem remains in ram (as I remember, multi-reference qchem tends to be ... large ...) then you may find that your performance is more dominated by memory access patterns, for which Barcelona might be better. If you were doing pure DFT, well, that can, for some problems, fit almost entirely in cache. In which case, it makes sense to get the largest cache chip you can get. As usual, real use case tests are the most realistic predictor of performance. Joe , Andy -- Joseph Landman, Ph.D Founder and CEO Scalable Informatics LLC, email: landman at scalableinformatics.com ...
The importance of electrostatic interactions in soft matter and biological systems can often be traced to non-uniform charge effects, which are commonly described using a multipole expansion of the corresponding charge distribution. The standard approach when extracting the charge distribution of a given system is to treat the constituent charges as points. This can, however, lead to an overestimation of multipole moments of high order, such as dipole, quadrupole, and higher moments. Focusing on distributions of charges located on a spherical surface - characteristic of numerous biological macromolecules, such as globular proteins and viral capsids, as well as of inverse patchy colloids - we develop a novel way of representing spherical surface charge distributions based on the von Mises-Fisher distribution ...
I spent a couple days at the Schrödinger User Symposium in Portland recently. I was really impressed with the topics presented at the conference. I was humbled at how little I know about computational chemistry, but I appreciate the geniuses working in drug discovery. For example, one speaker (Michael Podvinec) shared about the development of drugs to treat a viral infection called Dengue Fever. This disease affects 50 million people and kills 12,000 per year . The people working on a cure or vaccine for this and other deadly diseases analyze complex 3D molecules to determine whether compounds can perform a needed function. Although I dont understand More… 3D , stereoscopic , molecular modeling , Schrödinger , computational chemistry ...
The light chain CDR1 (LCDR1) loop of FI6v3 makes two contacts with the side of helix A, opposite the side that contributes to the hydrophobic groove; Phe27D makes hydrophobic contact with the aliphatic part of Lys39, and Asn28 hydrogen bonds to Asn43, together accounting for a buried surface area of about 190 Å2 for both H1 and H3. With H1 HA, which was cocrystallized in the uncleaved form, LCDR1 also makes extensive contact with the uncleaved "fusion peptide" of the neighboring HA monomer (Fig. 3, B and C, and Fig. 4, A and B), which accounts for an additional 320 Å2 of FI6v3 buried surface. Residues 28 and 29 of LCDR1 make main-chain amide hydrogen bonds with the main-chain carbonyls of HA1 residue 329 and the next-but-one residue, Leu2, of HA2 and thus span the cleavage site. Phe27D of LCDR1 makes hydrophobic contacts with Leu2 of the neighboring HA2, whereas the side-chain hydroxyl of Tyr29 hydrogen bonds to the main-chain carbonyl of residue 325 of the neighboring HA1 chain. In contrast ...
An apparatus and method for treating obesity and for delivering time-released medicaments is described and which includes a plurality of space-filling portions which are sized to be received within a human patients body and which come together in a patients body to form a structure which provides therapeutic benefit to the patient. In the method of the present invention, the method includes providing a plurality of space-filling portions which are sized to be received within the patients body; and inserting the space-filling portions into the body of the patient and wherein the respective space-filling portions come together following insertion into the body to form a structure providing therapeutic benefit to the patient.
The usual conference conversation starts with "Hey X, how are things going?", "Oh, fine, and you?", "Oh, fine." But one person responded "Writing a lot of proposals and getting them rejected." I really appreciated this honesty, and it makes me feel less bad about my own rejections. A few weeks ago I had a similar talk with another colleagues about the possibility of having no PhD students in the not-too-distant future and how this affects the choice of research projects one can take on. I think a lot of scientists are going through the same type of thing and it is important to be open about it ...
title: A system for collecting and curating sightseeing information toward satisfactory tour plan creation abstract: Satisfactory tour planning entails providing tourists with tour plans that reflect both static information, such as tourists preferences and profiles; and dynamic information, such as crowded sightseeing spots and congested paths to these spots. Collecting, maintaining, and curating such dynamic information imposes a lot of time, monetary, and labor costs on those who manage tourist spots and the tourists themselves. In this paper, we propose a system that uses two novel mechanisms: (1) a participatory collection mechanism that efficiently and timely collects and updates both static and dynamic information about tourist spots and paths; and (2) a content curation mechanism that selects important items from the collected information and compiles them into tour plans. We conducted a pilot study where two categories of people, those who make plans before sightseeing and those who do ...
CCH is an overlay journal that identifies the most important papers in computational and theoretical chemistry published in the last 1-2 years. CCH is not affiliated with any publisher: it is a free resource run by scientists for scientists. You can read more about it here ...
CCH is an overlay journal that identifies the most important papers in computational and theoretical chemistry published in the last 1-2 years. CCH is not affiliated with any publisher: it is a free resource run by scientists for scientists. You can read more about it here ...
The peptide bond has considerable double-bond character and this prevents rotation around that bond in the polypeptide chain. Adjacent amino acids can adopt different configurations by rotation around the two other bonds in the backbone. The angle of the bond between the nitrogen atom (blue) and the α-carbon atom (black) is Φ (phi) and the angle of the bond between the α-carbon atom and the carbonyl carbon atom (grey) is Ψ (psi) [The Peptide Bond]. These angles are measured in degrees where 180° is the angle of the bonds when all of the atoms of both residues lie in the most extended conformation. Rotation in one direction is positive so the values go from 0° to 180° and in the other direction they go from 0° to -180°. (180° = -180° in this notation ...
Franz Joseph Gall 1758-1828 was he could predict a buy Reviews ins house by autoantibody-producing mice on their use. In 1796 he contributed a role of the many land. This microfluidic buy signed hemorrhagic in the Such manner, well in the USA.
L-leucine 4-methoxy-beta-naphthylamide hydrochloride;4467-68-9;H-leu-4m-betana hcl;H-leu-4mbna hcl;L-leu-4-methoxy-beta-naphthylamide hcl;L-leucine 4-methoxy-beta-naphthylamide hydrochloride;L-leucyl-4-methoxy-beta-naphthylamide hydrochloride;TS77403.Tetrahedron
Dispersion-corrected DFT, such as B3LYP-D3, are not new functionals but a mix of conventional functionals and an add-on energy term. For example, B3LYP-D3 denotes a calculation with the usual B3LYP functional plus a D3 dispersion correction energy term. The dispersion correction energy term is a relatively simply function of interatomic distances and contain adjustable parameters that are fitted to conformational and interaction energies computed using CCSD(T)/CBS. The fitting is done for a given functional. DFT-D and DFT-D2 energy corrections consider all pairs of atoms while DFT-D3 also consider triplets of atoms to account for three-body effects ...
Enzymes are nanomachines that are exceptionally efficient at catalyzing a chemical reaction. They play a role in all cellular mechanisms. Like all proteins, they are made up of amino acid chains that are folded and assembled in a very precise 3D structure. Some enzymes, like ribonuclease A, are so efficient that they catalyze the transformation of chemical molecules thousands of times per second.. In this study, Donald Gagné, a researcher in Professor Doucets lab holding a PhD in biology from INRS, analyzed the impact of removing a methyl group located near a loop distant from the reaction site of ribonuclease A-a very slight change that presumably would have no effect. The mutation does not perturb the 3D structure of the enzyme. However, it did result in a four-fold reduction in the affinity of ribonuclease A for nucleotides (molecules to which it must bind to carry out its function). How is this possible?. Using crystallography techniques and nuclear magnetic resonance to examine the enzyme ...
Hydrophobic • Aromatic face-to-face • Aromatic face-to-edge • H-bond donor • H-bond acceptor • Ionic positive • Ionic negative ...
Residues present on the surface of the proteins are involved in a number of functions, especially in ligand-protein interactions, that are important for drug design. The residues present in the core of the protein provide stability to the protein and help in maintaining protein structure. Hence, there is a need for a binary characterization of protein residues based on their surface accessibility (surface accessible or buried). Such a classification can aid in the directed study of either residue type. A number of methods for the prediction of surface accessible protein residues have been proposed in the past. However, most of these methods are computationally complex and time consuming. In this thesis, we propose a simple method based on protein sequence homology parameters for the binary classification of protein residues as surface accessible or "buried". To aid in the classification of protein residues, we chose three highly conservative homology-based parameter filter thresholds. The filter ...
A technique for identifying folding patterns of proteins using mass spectrometry that is potentially faster and requires less sample than X-ray crystallographic or NMR methods has been developed by B.W. Gibson and I.D. Kuntz. They believe the time needed to determine the fold family of a protein can be reduced to one week and that less than 10mg of protein may be required to elucidate macromolecular interactions, and multiple conformational states, and to contribute to the design of protein mimetics ...
My docking experiments of OSM-S-106 vs all crystal structures of Plasmodium kinases supports PKA (protein kinase A) as the top target (PDB 5kbf).. OSM-S-106 was docked into the ligand binding site with the target side chains free to rotate as described in the previous entry. The docked structure was then energy minimized in Yasara with the Yasara2 force field with explicit water molecules in a 6A dodecahedral box. Three cycles of simulated annealing energy minimization were performed. The energy minimized coordinates are attached. Visual inspection showed that OSM-S-106 was bound quite tightly in its pocket, especially the sulfonamide end, leaving little room for chemical extension. This would be consistent with the SAR data.. All the compounds in Series 3 were then aligned to the cAMP site using a combined ligand-based and force-field based method in Cresset Forge, with protein structure (pdb 5kbf) set as medium strength restraints. I then created a number of modifications of OSM-S-106 that I ...
Profacgen, a US-based biotech company, has added one additional molecular modeling service, protein structure modeling, to its existing custom protein services.. The three-dimensional structure of a protein provides essential information about its biological function and facilitates the design of therapeutic drugs that specifically bind to the protein target. Recent years have witnessed a tremendous increase in the number of experimentally determined protein structures. It is, however, still generally tedious and time-consuming to solve protein structures with experimental approaches. Therefore, computational approaches represent an alternative and supplement to experimental methods to obtain three-dimensional structure of a protein.. By taking advantages of computational modeling methods, Profacgen is able to predict the three-dimensional structure of proteins of its customers interest. Over the years, Profacgen has accumulated abundant experience with the modeling of various kinds of ...
The current status of docking procedures for predicting protein-protein interactions starting from their three-dimensional (3D) structure is reassessed by evaluating blind predictions, performed during 2003-2004 as part of Rounds 3-5 of the community-wide experiment on Critical Assessment of PRedicted Interactions (CAPRI). Ten newly determined structures of protein-protein complexes were used as targets for these rounds. They comprised 2 enzyme-inhibitor complexes, 2 antigen-antibody complexes, 2 complexes involved in cellular signaling, 2 homo-oligomers, and a complex between 2 components of the bacterial cellulosome. For most targets, the predictors were given the experimental structures of 1 unbound and 1 bound component, with the latter in a random orientation. For some, the structure of the free component was derived from that of a related protein, requiring the use of homology modeling. In some of the targets, significant differences in conformation were displayed between the bound and ...
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Notice that the helix content rises and falls several times without any trace of it appearing on the RMSD curve. This is because large RMSD values such as 20 Å can result from completely unstructured chains as well as "unbundled" folded helices. Notice also that the hydrogen bond energy is related almost trivially with the helix content. The most probable hydrogen bonds in this system are those associated with the α-helices. Notice that the hydrophobicity energy only reaches its optimum values when the RMSD reaches the native-like values, whereas hydrogen bond (in the left figure) saturates a little before that. Taken together, these plots point towards a folding process in which the helices form independently, before being assembled into a 3-helix bundle. The helix formation is driven mainly by hydrogen bonds where as arrangement of the folded helices is driven by hydrophobicity. ...
The mechanisms by which JAK2 is activated by the prevalent pseudokinase (JH2) V617F mutation in blood cancers remain elusive. Via structure-guided mutagenesis and transcriptional and functional assays, we identify a community of residues from the JH2 helix αC, SH2-JH2 linker and JH1 kinase domain that mediate V617F-induced activation. This circuit is broken by altering the charge of residues along the solvent-exposed face of the JH2 αC, which is predicted to interact with the SH2-JH2 linker and JH1. Mutations that remove negative charges or add positive charges, such as E596A/R, do not alter the JH2 V617F fold, as shown by the crystal structure of JH2 V617F E596A. Instead, they prevent kinase domain activation via modulation of the C-terminal residues of the SH2-JH2 linker. These results suggest strategies for selective V617F JAK2 inhibition, with preservation of wild type function. ...
Molecular dynamics (MD) simulation is a technique that aids in the understanding of fundamental processes in biology and chemistry, and has important technological applications in pharmacy, biotechnology, and nanotechnology. Many complex molecular processes have cascades of timescales spanning the range from 10-15 s to 1 s, often with no pronounced gap that would permit efficient coarse-grained time integration.. In many applications, the slowest timescales and the associated structural rearrangements are the ones of interest. In this project, we study the challenging process of induced folding of peptides. Such states may be found when peptide ligands bind to proteins and when membrane-associated proteins anchor into the membrane. Here, association and conformational changes occur on physical timescales of nano- to milliseconds, while dissociation events may require seconds or longer.. The long-term aims of this project are to develop efficient modeling and simulation methods for the dominant ...
Given some similarity in sequence between two proteins, a molecular model can be constructed for one sequence provided that the tertiary structure of the other is known. This approach, which is often...
Protein folding prediction is a non-convex optimization problem very relevant in biology. It consists in predicting the three dimensional structure of a protein molecule starting from the sequence information alone. The complexity of this problem arises from many sources: in the first place the search space is huge because an astonishing number of different conformations have to be considered in order to find the currect one. In second place evaluating each model is hard since thousands of atomic interactions have to be computed during and the energy description currently available is only an approximation of the true energy. Many large scale projects have been established to develop PSP tools and to perform predictions of real protein structures using both supercomputers and distributed computing , nevertheless the key to achieve reliable predictions is yet to be found. Simplified representation models such as the HP model (bottom right) preserve a considerable complexity (HP-PSP is NP-hard) ...
multihelical; 3-helical bundle similar to one half of the DEATH domain fold is flanked by two alpha-hairpins forming a four-helical bundle; the axes of the three-helical and four-helical bundles are aproximately orthogonal to each other ...
Bcl-xL is a member of the Bcl-2 family of apoptotic regulators, responsible for inhibiting the permeabilization of the mitochondrial outer membrane, and a promising anti-cancer target. Bcl-xL exists in the following conformations, each believed to play a role in the inhibition of apoptosis: (a) a soluble folded conformation, (b) a membrane-anchored (by its C-terminal α8 helix) form, which retains the same fold as in solution and (c) refolded membrane-inserted conformations, for which no structural data are available. Previous studies established that in the cell Bcl-xL exists in a dynamic equilibrium between soluble and membranous states, however, no direct evidence exists in support of either anchored or inserted conformation of the membranous state in vivo. In this in vitro study, we employed a combination of fluorescence and EPR spectroscopy to characterize structural features of the bilayer-inserted conformation of Bcl-xL and the lipid modulation of its membrane insertion transition. Our ...

Contacts: Karen McNulty Walsh, (631) 344-8350 or Peter Genzer, (631) 344-3174printerPrint

Scientists Reveal Details of Calcium Safety-Valve in Cells

Structure of membrane protein that plays a role in signaling cell death could be new target for anticancer drugs

June 6, 2014

A solution NMR-derived structure of a new long -acting, B31(Lys)-B32(Arg) (LysArg), engineered human insulin monomer, in H(2)O/CD(3)CN, 65/35 vol %, pH 3.6, is presented and compared with the available X-ray structure of a monomer that forms part of a hexamer (Smith, et al., Acta Crystallogr D 2003, 59, 474) and with NMR structure of human insulin in the same solvent (Bocian, et al., J Biomol NMR 2008, 40, 55-64). Detailed analysis using PFGSE NMR (Pulsed Field Gradient Spin Echo NMR) in dilution experiments and CSI analysis prove that the structure is monomeric in the concentration range 0.1-3 mM. The presence of long-range interstrand NOEs in a studied structure, relevant to the distances found in the crystal structure of the monomer, provides the evidence for conservation of the tertiary structure. Therefore the results suggest that this solvent system is a suitable medium for studying the native conformation of the protein, especially in situations (as found for insulins) in which extensive ...
New, license-free DNA ladders will allow researchers to estimate the size of fragments of DNA for a fraction of the cost of currently available methods.
We have developed a new method for the building of pharmacophores for G protein-coupled receptors, a major drug target family. The method is a combination of the ligand- and target-based pharmacophore methods and founded on the extraction of structural fragments, interacting ligand moiety and receptor residue pairs, from crystal structure complexes. We describe the procedure to collect a library with more than 250 fragments covering 29 residue positions within the generic transmembrane binding pocket. We describe how the library fragments are recombined and inferred to build pharmacophores for new targets. A validating retrospective virtual screening of histamine H1 and H3 receptor pharmacophores yielded area-under-the-curves of 0.88 and 0.82, respectively. The fragment-based method has the unique advantage that it can be applied to targets for which no (homologous) crystal structures or ligands are known. 47% of the class A G protein-coupled receptors can be targeted with at least four-element ...
Ten lowest-energy conformers (best 20%) from the plainQ calculation. Depictions are as in Figure 6, but the Ca2+ ions are also shown, as gray spheres. The non-c
Substrate cleavage by metalloproteinases involves nucleophilic attack on the scissile peptide bond by a water molecule that is polarized by a catalytic metal, usually a zinc ion, and a general base, usually the carboxyl group of a glutamic acid side chain
XlaeOBP peptides corresponding to putative epitopes thought to be localized outside the OBP hydrophobic binding pocket and exhibiting the right calculated antigenicity were chosen as sequences C64Qâ  Y79. They were synthesized, both conjugated to ...
In the compound interacts while using the Cys496, that is extremely exclusive on the Etk. Only eight kinases from the 491 kinases which were analyzed inside a previous review [29,30] present Threonine and Cysteine at these positions. Hence CTA095s conversation with the two Thr489 and Cys496 may possibly present it with exceptional kinase selectivity. We also employed LigPlot to forecast hydrogen bonding andor hydrophobic interactions in the binding pocket, and our results confirmed that many hydrophobic interactions are responsible for that CTA095-Etk binding (Determine S3A and S3B). Aspect chains that putatively interact with CTA095 are proven in Determine S3C. Examination on the molecular dynamics trajectories also demonstrate which the R3 team as well as three-ring main interact strongly and stably while using the facet chains during the binding pocket, while R1 and areas of R2 are solvent uncovered, and mayPLOS A person , www.plosone.orgserve as targets for further more improvement on the ...
Actually, the structural deciphering of PII signaling is another of our key goals. PII is a very ancient, conserved, and widespread signaling protein (although not found in animals) that transduces carbon/energy/nitrogen abundance signals. It interacts with protein targets, including channels, enzymes and gene regulators, and it is controlled allosterically and by covalent modification. Thus, PII is the center of a wide regulatory universe that includes control of PII by a complex machinery, and control by PII of many key processes like membrane passage, metabolic pathways, transcription regulation and even signaling by other proteins. We believe that the detailed structural knowledge of this regulatory network is essential, since, in addition to its intrinsic interest, it might provide key clues for manipulating many important processes of biotechnological and even ecological and public health interest. Another chunk of our work deals with the catalysts of the urea cycle and of arginine ...
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A skeleton equation again provides limited information. It tells you what the chemical formulas are for the reactants and products, but again it tells you nothing about how much. If you observe the skeleton equation above carefully, youll see that there is 1 Mg atom on the left and 1 Mg atom on the right. At least that part is balanced. There is however, 2 O atoms on the left and 1 O atom on the right. If even one atom does not match up evenly on both sides then the equation is unbalanced. ...
The integrated style guide is a newer project, derived from DIM with the goal to provide a wiki-like experience to the style guide development. That is the UI that allows to add new rules in the style guide was developed to work for both the oXygen desktop and for the oXygen web author, so the content of the style guide can be edited online, and we also re-publish the style guide automatically using GitHub pages after any change on the master branch. The published style guide contain "edit" links for each topic, and this coupled to the automatic publishing gives the wiki-like interaction ...
COMMUNICATIONS Gary, M. Meyer. New J. Chem. 1995, 19, 409; J.-C. Chambron, %-ChardonNoblat. A. Harriman, V. Heitz, J.-P. Sauvage, Pure Appl. Chem. 1993,65,2343, N Solladie, J.-C. Chamhron, C. 0. Dietrich-Buchecker, J -P. Sauvage. Angew. Chenz. 1996, 108, 951; Angew. Chem. In:. Ed. Engl. 1996, 35, 906. [9] G. S . Hanan, C. R. Arana, J.-M. Lehn, D. Fenske, Angew. Chem. 1995. 107, 1191; Angew. Chem. Inr. Ed. Engl. 1995,34. 1122, G. S. Hanan, C R. Arana, J.-M. Lehn, G . Baum, D. Fenske, Chem. Eur. J 1996,2, 1292. [lo] H. Sleiman, P. N. W. Baxter, J.-M. Lehn, K. Rissanen, J. Clzem. SOC.Chem. Commun. 1995,715. Ill] P. N. W. Baxter, J.-M. Lehn, I. Fischer, M:T. Youinou, Angew. Chem. 1994, 106, 2432; Angew. Chcm. Inl. Ed. EngI. 1994,33,2284. [12] C. 0. Dietrich-Buchecker, J.-P. Sauvage, Terruhedron 1990, 46, 503. [I31 Crystal structure data for [I(H,0)](PF,),.3C6H,.CH,N0,, M, = 2979.346 (the crystallographically determined value for M, was 2977.24, since the positions of the H atoms of the included ...