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
Experimental and computational studies have indicated that hydrophobicity plays a key role in driving the insertion of transmembrane alpha-helices into lipid bilayers. Molecular dynamics simulations allow exploration of the nature of the interactions of transmembrane alpha-helices with their lipid bilayer environment. In particular, coarse-grained simulations have considerable potential for studying many aspects of membrane proteins, ranging from their self-assembly to the relation between their structure and function. However, there is a need to evaluate the accuracy of coarse-grained estimates of the energetics of transmembrane helix insertion. Here, three levels of complexity of model system have been explored to enable such an evaluation. First, calculated free energies of partitioning of amino acid side chains between water and alkane yielded an excellent correlation with experiment. Second, free energy profiles for transfer of amino acid side chains along the normal to a phosphatidylcholine
Recent work has shown that polymeric micelles can template nanoparticles via interstitial sites in shear-ordered micelle solutions. In this work, we report results based on a coarse-grained molecular dynamics (CGMD) model of a solvent/polymer/nanoparticle system. Our results demonstrate the importance of pol
Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of selective anti-cancer agents. Here, the structure of the full-length H-Ras protein in complex with a 1,2-dimyristoylglycero-3-phosphocholine (DMPC) bilayer obtained from modeling and all-atom explicit solvent molecular dynamics simulations, as well as experimental validation of the main results, are presented. We find that, in addition to the lipid anchor, H-Ras membrane binding involves direct interaction of residues in the catalytic domain with DMPC phosphates. Two modes of binding (possibly modulated by GTP/GDP exchange) differing in the orientation and bilayer contact of the soluble domain as well as in the participation of the flexible linker in membrane binding are proposed. ...
TY - JOUR. T1 - Accelerating molecular dynamics simulations with population annealing. AU - Christiansen, Henrik. AU - Weigel, Martin. AU - Janke, Wolfhard. PY - 2019/2/15. Y1 - 2019/2/15. N2 - Population annealing is a powerful tool for large-scale Monte Carlo simulations. We adapt this method to molecular dynamics simulations and demonstrate its excellent accelerating effect by simulating the folding of a short peptide commonly used to gauge the performance of algorithms. The method is compared to the well established parallel tempering approach and is found to yield similar performance for the same computational resources. In contrast to other methods, however, population annealing scales to a nearly arbitrary number of parallel processors, and it is thus a unique tool that enables molecular dynamics to tap into the massively parallel computing power available in supercomputers that is so much needed for a range of difficult computational problems.. AB - Population annealing is a powerful ...
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.
Mechanical and Aerospace Engineering, ICMAE2011: Nanocomputational Observation of Interaction of Two Cytotoxins and Nanobio Membrane: Molecular Dynamics Simulation Study
The local hydrogen-bonding structure and dynamics of liquid water have been investigated using the Car-Parrinello molecular dynamics simulation technique. The radial distribution functions and coordination numbers around water molecules have been found to be strongly dependent on the number of hydrogen bonds formed by each molecule, revealing also the existence of local structural heterogeneities in the structure of the liquid. The results obtained have also revealed the strong effect of the local hydrogen-bonding network on the local tetrahedral structure and entropy. The investigation of the dynamics of the local hydrogen-bonding network in liquid water has shown that this network is very labile, and the hydrogen bonds break and reform very rapidly. Nevertheless, it has been found that the hydrogen-bonding states associated with the formation of four hydrogen bonds by a water molecule exhibit the largest survival probability and corresponding lifetime. The reorientational motions of water ...
Collagen mimetic peptides (CMPs) and collagen-like proteins (CLPs) that mimic either structural or functional characteristics of natural collagens hav..
We provide the parameters used in Umbrella Sampling simulations reported in our study "Efficient Estimation of Binding Free Energies between Peptides and an MHC Class II Molecule Using Coarse-Grained Molecular Dynamics Simulations with a Weighted Histogram Analysis Method", namely the set positions and spring constants for each window in simulations. Two tables are provided. Table 1 lists the names of the peptides and their corresponding sequences. Table 2 lists the parameters. The abstract of our work is the following: We estimate the binding free energy between peptides and an MHC class II molecule using molecular dynamics (MD) simulations with Weighted Histogram Analysis Method (WHAM). We show that, owing to its more thorough sampling in the available computational time, the binding free energy obtained by pulling the whole peptide using a coarse-grained (CG) force field (MARTINI) is less prone to significant error induced by biased-sampling than using an atomistic force field (AMBER). We ...
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
Fine! Back to the matter at hand, dimension reduction is an invaluable tool in modern computational chemistry because of the massive dimensionality of molecular dynamics simulations. To my knowledge, the biggest things being studied by MD currently are on the scale of the HIV-1 Capsid at 64 million atoms! Of course, these studies are being done on supercomputers, and for the most part studies are running on a much smaller number of atoms. For a thorough explanation of how MD simulations work, my Summer of Code colleague Fiona Naughton has an excellent and cat-filled post explaining MD and Umbrella Sampling. Why do we care about dynamics? As Dr. Cecilia Clementi mentions in her slides, Crystallography gives structures, but function requires dynamics!. A molecular dynamics simulation can be thought of as a diffusion process subject to drag (from the interactions of molecules) and random forces, (brownian motion). This means that the time evolution of the probability density of a molecule ...
FOLEY-MEYER Sarah, RAMSEYER Christophe, ENESCU Mironel - 2019 - Fate of cisplatin and its main hydrolysed forms in the presence of thiolates: a comprehensive computational and experimental study. - Metallomics. Article RAMSEYER Christophe, Yesylevskyy Semen, Savenko Mariia, Mura Simona, Couvreur Patrick - 2018 - Low density lipoproteins and human serum albumin as the carriers of squalenoylated drugs: insights from molecular simulations. - Molecular Pharmaceutics. Article Yesylevskyy Semen, RIVEL Timothée, RAMSEYER Christophe - 2017 - The influence of curvature on the properties of the plasma membrane. Insights from atomistic molecular dynamics simulations. - Scientific Reports. Article Yesylevskyy Semen, RIVEL Timothée, RAMSEYER Christophe, Yesylevskyy Semen O. - 2017 - Structures of single, double and triple layers of lipids adsorbed on graphene: Insights from all-atom molecular dynamics simulations. - Carbon. Article Sobot Dunja, Mura Simona, Yesylevskyy Semen O., Dalbin Laura, Cayre Fanny, ...
We use molecular dynamics simulations to study the crystallization of spherical nucleic-acid (SNA) gold nanoparticle conjugates, guided by sequence-specific DNA hybridization events. Binary mixtures of SNA gold nanoparticle conjugates (inorganic core diameter in the 8-15 nm range) are shown to assemble into BCC, CsCl, AlB2, and Cr3Si crystalline structures, depending upon particle stoichiometry, number of immobilized strands of DNA per particle, DNA sequence length, and hydrodynamic size ratio of the conjugates involved in crystallization. These data have been used to construct phase diagrams that are in excellent agreement with experimental data from wet-laboratory studies.. ...
Rhestr o setiau data » Ligand Field Molecular Dynamics Simulation of Pt(II)-Phenanthroline Binding to N-Terminal Fragment of Amyloid-beta Peptide [Data set] - Platts J, Turner M, Mutter ST, et al. (2017). Cardiff University. 10.5281/zenodo.1050388. Alzheimers Disease Molecular dynamics ...
Bio-catalytic micro- and nanomotors self-propel by the enzymatic conversion of substrates into products. Despite the advances in the field, the fundamental aspects underlying enzyme-powered self-propulsion have rarely been studied. In this work, we select four enzymes (urease, acetylcholinesterase, glucose oxidase, and aldolase) to be attached on silica microcapsules and study how their turnover number and conformational dynamics affect the self-propulsion, combining both an experimental and molecular dynamics simulations approach. Urease and acetylcholinesterase, the enzymes with higher catalytic rates, are the only enzymes capable of producing active motion. Molecular dynamics simulations reveal that urease and acetylcholinesterase display the highest degree of flexibility near the active site, which could play a role on the catalytic process. We experimentally assess this hypothesis for urease micromotors through competitive inhibition (acetohydroxamic acid) and increasing enzyme rigidity ...
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 behaviour of molecular hydrogen at high pressures has implications for the interiors of the giant planets, which consist mainly of hydrogen. In particular, the question of whether solid hydrogen becomes metallic under these conditions has been much debated1-9, in part because the structure that molecular hydrogen adopts at high pressure is not known. Here we report the results of first-principles molecular dynamics simulations of solid hydrogen at pressures up to 270 GPa. We find that at 77 K, hydrogen exists as a stable, orientationally disordered phase up to 60 GPa, consistent with experimental results1,10. As the presssure is raised, a gradual transformation to an ordered orthorhombic structure begins at 160 GPa, and by 260 GPa the solid becomes semi-conducting, with an indirect band gap of 1.4eV. The calculated vibrational density of states of this phase is consistent with infrared and Raman spectra measured up to 160 GPa (ref. 11). Although limitations on the simulation time and size may result
Molecular dynamics simulations of a phospholipid-detergent mixture. An improved empirical potential energy function for molecular simulations of phospholipids
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We explore this process through modeling the wrapping of a spherical particle by a model bilayer membrane, using coarse-grained molecular dynamics simulations and a theoretical elastic model. Specifically, we study the kinetics and morphologies of wrapping as a function of the relevant system parameters, including the particle radius, the strength of the membrane-particle interaction, and the membrane bending rigidity. The theoretical model predicts a phase diagram as a function of the system parameters, which is compared to results of the dynamics simulations ...
Mechanical properties of copper (Cu) film under grinding process were accomplished by molecular dynamics simulation. A numerical calculation was carried out to understand the distributions of atomic and slip vector inside the Cu films. In this study, the roller rotation velocity, temperature, and roller rotation direction change are investigated to clarify their effect on the deformation mechanism. The simulation results showed that the destruction of materials was increased proportionally to the roller rotation velocity. The machining process at higher temperature results in larger kinetic energy of atoms than lower temperature during the grinding process of the Cu films. The result also shows that the roller rotation in the counterclockwise direction had the better stability than the roller rotation in the clockwise direction due to significantly increased backfill atoms in the groove of the Cu film surface. Additionally, the effects of the rolling resistances on the Cu film surfaces during the
Mechanical properties of copper (Cu) film under grinding process were accomplished by molecular dynamics simulation. A numerical calculation was carried out to understand the distributions of atomic and slip vector inside the Cu films. In this study, the roller rotation velocity, temperature, and roller rotation direction change are investigated to clarify their effect on the deformation mechanism. The simulation results showed that the destruction of materials was increased proportionally to the roller rotation velocity. The machining process at higher temperature results in larger kinetic energy of atoms than lower temperature during the grinding process of the Cu films. The result also shows that the roller rotation in the counterclockwise direction had the better stability than the roller rotation in the clockwise direction due to significantly increased backfill atoms in the groove of the Cu film surface. Additionally, the effects of the rolling resistances on the Cu film surfaces during the
The dimerization of the cationic β-hairpin antimicrobial peptide protegrin-1 (PG1) is investigated in three different environments: water, the surface of a lipid bilayer membrane, and the core of the membrane. PG1 is known to kill bacteria by forming oligomeric membrane pores, which permeabilize the cells. PG1 dimers are found in two distinct, parallel and antiparallel, conformations, known as important intermediate structural units of the active pore oligomers. What is not clear is the sequence of events from PG1 monomers in solution to pores inside membranes. The step we focus on in this work is the dimerization of PG1. In particular, we are interested in determining where PG1 dimerization is most favorable. We use extensive molecular dynamics simulations to determine the potential of mean force as a function of distance between two PG1 monomers in the aqueous subphase, the surface of model lipid bilayers and the interior of these bilayers. We investigate the two known distinct modes of dimerization
Ammonia transfer from the glutamine site to the fructose-6P site of bacterial glucosamine-6-phosphate synthase was studied by molecular dynamics simulations. The studies suggest a key role for Trp74, in the sealing of the hydrophobic channel connecting the two binding sites, as well as for the two Ala602 and Val605 residues, which form a narrow passage whose opening/closing constitutes an essential event in ammonia transfer. Kinetic analyses of the corresponding protein mutants confirmed our predictions. The efficiency of ammonia transfer which was close to zero in the W74A mutant was partially restored by increasing the size of the corresponding side-chain; the simulations performed on the W74A mutant suggested the formation of a hole in the channel. In the case of A602L and V605L mutants, the efficiency of ammonia transfer decreased to 50% of the value of the native protein. None of the mutants were, however, able to use exogenous ammonia as a substrate.
Accurate estimation of protein-carbohydrate binding energies using computational methods is a challenging task. Here we report the use of expanded ensemble molecular dynamics (EEMD) simulation with double decoupling for estimation of binding energies of hevein, a plant lectin with its monosaccharide and disaccharide ligands GlcNAc and (GlcNAc)(2), respectively. In addition to the binding energies, enthalpy and entropy components of the binding energy are also calculated. The estimated binding energies for the hevein-carbohydrate interactions are within the range of +/- 0.5 kcal of the previously reported experimental binding data. For comparison, binding energies were also estimated using thermodynamic integration, molecular dynamics end point calculations (MM/GBSA) and the expanded ensemble methodology is seen to be more accurate. To our knowledge, the method of EEMD simulations has not been previously reported for estimating biomolecular binding energies.. ...
In this thesis a computational complement to experimental observables will be presented. Computational tools such as molecular dynamics and quantum chemical tools will be used to aid in the interpretation of experimentally (NMR) obtained structural data. The techniques are applied to study the dynamical features of biologically important carbohydrates and their interaction with proteins. When evaluating conformations, molecular mechanical methods are commonly used. Paper I, highlights some important considerations and focuses on the force field parameters pertaining to carbohydrate moieties. Testing of the new parameters on a trisaccharide showed promising results. In Paper II, a conformational analysis of a part of the repeating unit of a Shigella flexneri bacterium lipopolysaccharide using the modified force field revealed two major conformational states. The results showed good agreement with experimental data. In Paper III, a trisaccharide using Langevin dynamics was investigated. The ...
NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126.
We enabled an unprecedented scale of quantum molecular dynamics simulations through algorithmic innovations. A new lean divide-and-conquer density function
We have performed molecular dynamics simulations for a total duration of more than 10 µs (with most molecular trajectories being 1 µs in dura
URAHATA, Sergio Minoru; RIBEIRO, Mauro Carlos Costa. Molecular dynamics simulation of molten LiNO3 with flexible and polarizable anions. Physical Chemistry Chemical Physics, London, v. 5, n. 12, p. 2619-2624, 2003. DOI: 10.1039/b303713d ...
The team brought together data gathered using X-ray crystallography, NMR spectroscopy, cryoelectron microscopy, and lipidomics into whats called a "coarse-grained molecular dynamics simulation." This technique allows the model virus to be put through different virtual environments, each having varying temperatures and lipid compositions. The current simulations are still quite limited, but the technique should lead to more complicated tests involving potential therapies and different chemical agents ...
Simulation Parameters used in the Study titled Efficient Estimation of Binding Free Energies between Peptides and an MHC Class II Molecule Using Coarse-Grained Molecular Dynamics Simulations with a Weighted Histogram Analysis Method ...
NaChBac was the first discovered bacterial sodium voltage-dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work, a pore-only construct built using the NavMs template was investigated using unbiased molecular dynamics and metadynamics. The potential of mean force (PMF) from the unbiased run features four minima, three of which correspond to sites IN, CEN, and HFS discovered in NavAb. During the run, the selectivity filter (SF) is spontaneously occupied by two ions, and frequent access of a third one is often observed. In the innermost sites IN and CEN, Na+ is fully hydrated by six water molecules and occupies an on-axis position. In site HFS sodium interacts with a glutamate and a serine from the same subunit and is forced to adopt an off-axis placement. Metadynamics simulations biasing one and two ions show an energy barrier in the SF that prevents single-ion permeation. An analysis of the permeation mechanism was performed both ...
Car-Parrinello molecular dynamics or CPMD refers to either a method used in molecular dynamics (also known as the Car-Parrinello method) or the computational chemistry software package used to implement this method. The CPMD method is related to the more common Born-Oppenheimer molecular dynamics (BOMD) method in that the quantum mechanical effect of the electrons is included in the calculation of energy and forces for the classical motion of the nuclei. However, whereas BOMD treats the electronic structure problem within the time-independent Schrödinger equation, CPMD explicitly includes the electrons as active degrees of freedom, via (fictitious) dynamical variables. The software is a parallelized plane wave / pseudopotential implementation of density functional theory, particularly designed for ab initio molecular dynamics. The Car-Parrinello method is a type of molecular dynamics, usually employing periodic boundary conditions, planewave basis sets, and density functional theory, proposed ...
Membrane protein structures are underrepresented in the Protein Data Bank (PDB) due to difficulties associated with expression and crystallization. As such, it is one area where computational studies, particularly Molecular Dynamics (MD) simulations, can provide useful additional information. Recently, there has been substantial progress in the simulation of lipid bilayers and membrane proteins embedded within them. Initial efforts at simulating membrane proteins embedded within a lipid bilayer were relatively slow and interactive processes, but recent advances now mean that the setup and running of membrane protein simulations is somewhat more straightforward, though not without its problems. In this chapter, we outline practical methods for setting up and running MD simulations of a membrane protein embedded within a lipid bilayer and discuss methodologies that are likely to contribute future improvements.
This thesis focuses on the applications of molecular dynamics simulation techniques in the fields of solution chemistry and atmospheric chemistry. The work behind the thesis takes account of the fast development of computer hardware, which has made computationally intensive simulations become more and more popular in disciplines like pharmacy, biology and materials science. In molecular dynamics simulations using classical force fields, the atoms are represented by mass points with partial charges and the inter-atomic interactions are modeled by approximate potential functions that produce satisfactory results at an economical computational cost. The three-dimensional trajectory of a many-body system is generated by integrating Newtons equations of motion, and subsequent statistical analysis on the trajectories provides microscopic insight into the physical properties of the system.. The applications in this thesis of molecular dynamics simulations in solution chemistry comprise four aspects: ...
Christopher D. Snow, Bojan Zagrovic, and Vijay S. Pande. Journal of the Americal Chemical Society (2002). ABSTRACT: A number of rapidly folding proteins have been characterized in recent years.1 These small proteins can provide the first direct comparisons between simulated and experimental protein folding kinetics and pathways. Proteins have been characterized through thermodynamic sampling methods, unfolding simulations, and folding simulations using simple potentials. Here, as described recently, we use several thousand stochastic dynamics simulations in a generalized-Born implicit solvent (in atomic detail) to simulate the folding dynamics of the Trp cage mini-protein under experimental conditions (27 °C with full solvent viscosity,) 91 ps-1). The [email protected] distributed computing project was used to generate an aggregate simulation time of ~100 us (~250 CPU years). First we capture the rapid relaxation from an extended starting condition to a relaxed unfolded state ensemble of thousands ...
We are developing a method for studying the structural dynamics of biomolecules, which couples fluorescence spectroscopy and computational modeling, providing a more complete understanding than is possible with either technique alone. The computational modeling will be based primarily on molecular dynamics (MD) simulation. Before running MD, dye parameters were determined that are consistent with the Cornell et al. force field (1995, J. Am. Chem. Soc.) and the generalized AMBER force field (GAFF; Wang et al., 2004, J. Comput Chem.) commonly used in AMBER. Parameterization was carried out using quantum mechanical calculations to determine low-energy conformers of the dyes and to calculate electrostatic potentials for these conformers. The RESP charge fitting procedure was used to derive atomic charges. All other parameters were assigned by analogy to pre-existing force field parameters. Several DNA- and RNA-fluorescent probe systems will be explicitly solvated in water and equilibrated before beginning
All-atom molecular dynamics simulations can provide insight into the properties of polymeric gene-delivery carriers by elucidating their interactions and detailed binding patterns with nucleic acids. However, to explore nanoparticle formation through complexation of these polymers and nucleic acids and study their behavior at experimentally relevant time and length scales, a reliable coarse-grained model is needed. Here, we systematically develop such a model for the complexation of small interfering RNA (siRNA) and grafted polyethyleneimine copolymers, a promising candidate for siRNA delivery. We compare the predictions of this model with all-atom simulations and demonstrate that it is capable of reproducing detailed binding patterns, charge characteristics, and water release kinetics. Since the coarse-grained model accelerates the simulations by one to two orders of magnitude, it will make it possible to quantitatively investigate nanoparticle formation involving multiple siRNA molecules and ...
The search for new and more efficient glycoside hydrolases (GH) has intensified over the last few years due to a need for such enzymes in the biofuel industry. Man5B, a cytoplasmic enzyme of the glycoside hydrolase family 5, has been shown to cleave manno- and gluco-oligosaccharides into mono- and disaccharides for subsequent metabolism[5]. Experimental assays show that Man5B acts more efficiently on manno-oligosaccharides than on gluco-oligosaccharides, however the mechanism for this behavior was not clear. We have performed a molecular dynamics study to identify this mechanism and to elucidate which amino acid residues are controlling enzymatic efficiency. The insights gained from these studies are critical to the development of more efficient enzymes through rational targeting of residues for site-directed mutagenesis.. The molecular dynamics simulations yielded surprising results in that they showed Man5B to bind cellohexaose nearly as tightly as mannohexaose, as shown in Figure 3A. The RMSD ...
A molecular dynamics study of structure and short-time dynamics of water in kaolinite. Using molecular dynamics to simulate electronic spin resonance spectra of T4 Lysozyme
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Motivation: Membrane fusion constitutes a key stage in cellular processes such as synaptic neurotransmission and infection by enveloped viruses. Current experimental assays for fusion have thus far been unable to resolve early fusion events in structural detail. We have previously used molecular dynamics simulations to develop mechanistic models of fusion by small lipid vesicles. Here, we introduce a novel structural measurement of vesicle topology and fusion geometry: persistent voids. Results: Persistent voids calculations enable systematic measurement of structural changes in vesicle fusion by assessing fusion stalk widths. They also constitute a generally applicable technique for assessing lipid topological change. We use persistent voids to compute dynamic relationships between hemifusion neck widening and formation of a full fusion pore in our simulation data. We predict that a tightly coordinated process of hemifusion neck expansion and pore formation is responsible for the rapid vesicle ...
The importance of taking into account protein flexibility in drug design and virtual ligand screening (VS) has been widely debated in the literature, and molecular dynamics (MD) has been recognized as one of the most powerful tools for investigating intrinsic protein dynamics. Nevertheless, deciphering the amount of information hidden in MD simulations and recognizing a significant minimal set of states to be used in virtual screening experiments can be quite complicated. Here we present an integrated MD-FLAP (Molecular Dynamics - Fingerprint for Ligand and Proteins) approach, comprising a pipeline of Molecular Dynamics, Clustering and Linear Discriminant Analysis, for enhancing accuracy and efficacy in VS campaigns. We first extracted a limited number of representative structures from tens of ns of MD trajectories by means of the k-medoids clustering algorithm as implemented in the BiKi Life Science Suite.1 Then, instead of applying arbitrary selection criteria, i.e. RMSD, pharmacophore ...
We report here the interactions between a hydrophobic drug and a model cellular membrane at the molecular level using all-atom molecular dynamics simulations of paclitaxel, a hydrophobic cancer drug. The calculated free energy of a single drug across the bilayer interface displays a minimum in the outer hydrophobic zone of the membrane. The transfer free energy shows excellent agreement with reported experimental data. In two sets of long-time simulations of high concentrations of drug in the membrane (12 and 11 mol %), the drugs display substantial clustering and rotation with significant directional preference in their diffusion. The main taxane ring partitions in the outer hydrophobic zone, while the three phenyl rings prefer to be closer to the hydrophobic core of the membrane. The clustering of the drug molecules, order parameters of the lipid tails, and water penetration suggest that the fluidity and permeability of the membrane are affected by the concentration of drugs that it contains.
Purpose: : There are a number of human diseases which are linked to the failure of proper gap junction control. Mutations in PKCγ C1B domains are associated with Human Spinocerebellar Ataxia, SCA-14. The mutations lead to an impaired cellular response to extracellular signals and oxidative stress. The purpose of this research is to determine the structural influence of C1B domains mutations on the functional activation of PKCγ, a major lens PKC. Methods: : We used molecular dynamics simulations and the solved NMR structure to compare the energy-minimized structures of PKCγ WT and mutant proteins. We purified the C1B domain and several variants using a bacterial expression system and carried out multi-dimensional hetero-nuclear NMR. C1B domain mutations H101Y and S119P were introduced into a GST linked pGEX-6p vector and subsequently transfected into BLD-21 low competency E. coli cells. The fusion proteins were treated with lysate buffer and then clarified by centrifugation and filtration ...
We have studied the unfolding by force of one of the immunoglobulin domains of the muscle protein titin using molecular dynamics simulations at 300 K. Previous studies, done at constant pulling rates, showed that under the effect of the force two strands connected to each other by six backbone H-bon... DRIVER (German) ...