Application Of Molecular Dynamics Simulations Research Articles

Rapid parameterization of small molecules using the force field toolkit

The inability to rapidly generate accurate and robust parameters for novel chemical matter continues to severely limit the application of molecular dynamics simulations to many biological systems of interest, especially in fields such as drug discovery. Although the release of generalized versions of common classical force fields, for example, General Amber Force Field and CHARMM General Force Field, have posited guidelines for parameterization of small molecules, many technical challenges remain that have hampered their wide-scale extension. The Force Field Toolkit (ffTK), described herein, minimizes common barriers to ligand parameterization through algorithm and method development, automation of tedious and error-prone tasks, and graphical user interface design. Distributed as a VMD plugin, ffTK facilitates the traversal of a clear and organized workflow resulting in a complete set of CHARMM-compatible parameters. A variety of tools are provided to generate quantum mechanical target data, setup multidimensional optimization routines, and analyze parameter performance. Parameters developed for a small test set of molecules using ffTK were comparable to existing CGenFF parameters in their ability to reproduce experimentally measured values for pure-solvent properties (<15% error from experiment) and free energy of solvation (±0.5 kcal/mol from experiment).

Molecular dynamics simulations of amyloid fibrils: an &amp;lt;italic&amp;gt;in silico&amp;lt;/italic&amp;gt; approach

Amyloid fibrils play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease, type II diabetes mellitus, and the prion-related transmissible spongiform encephalopathies. The mechanism of fibril formation and protein aggregation is still hotly debated and remains an important open question in order to develop therapeutic method of these diseases. However, traditional molecular biological and crystallographic experiments could hardly observe atomic details and aggregation process. Molecular dynamics (MD) simulations could provide explanations for experimental results and detailed pathway of protein aggregation. In this review, we focus on the applications of MD simulations on several amyloidogenic protein systems. Furthermore, MD simulations could help us to understand the mechanism of amyloid aggregation and how to design the inhibitors.

Critical Assessment of Current Force Fields. Short Peptide Test Case.

The applicability of molecular dynamics simulations for studies of protein folding or intrinsically disordered proteins critically depends on quality of energetic functions-force fields. The four popular force fields for biomolecular simulations, CHARMM22/CMAP, AMBER FF03, AMBER FF99SB, and OPLS-AA/L, were compared in prediction of conformational propensities of all common proteinogenic amino acids. The minimalistic model of terminally block amino acids (dipeptides) was chosen for assessment of side chain effects on backbone propensities. The precise metadynamics simulations revealed striking inconsistency of trends in conformational preferences as manifested by investigated force fields for both backbone and side chains. To trace this disapproval between force fields, the two related AMBER force fields were studied more closely. In the cases of FF99SB and FF03, we uncovered that the distinct tends were driven by different charge models. Additionally, the effects of recent correction for side chain torsion (FF99SB-ILDN) were examined on affected amino acids and exposed significant coupling between free energy profiles and propensities of backbone and side chain conformers. These findings have important consequences for further force field development.

Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif

Protein farnesyltransferase (FTase) is an important target in many research fields, more markedly so in cancer investigation since several proteins known to be involved in human cancer development are thought to serve as substrates for FTase and to require farnesylation for proper biological activity. Several FTase inhibitors (FTIs) have advanced into clinical testing. Nevertheless, despite the progress in the field several functional and mechanistic doubts on the FTase catalytic activity have persisted. This work provides some crucial information on this important enzyme by describing the application of molecular dynamics simulations using specifically designed molecular mechanical parameters for a variety of 22 CaaX peptides known to work as natural substrates or inhibitors for this enzyme. The study involves a comparative analysis of several important molecular aspects, at the mechanistic level, of the behavior of substrates and inhibitors at the dynamic level, including the behavior of the enzyme and peptides, as well as their interaction, together with the effect of the solvent. Properties evaluated include the radial distribution function of the water molecules around the catalytically important zinc metal atom and cysteine sulfur of CaaX, the conformations of the substrate and inhibitor and the corresponding RMSF values, critical hydrogen bonds, and several catalytically relevant distances. These results are discussed in light of recent experimental and computational evidence that provides new insights into the activity of this enzyme.

On the estimation and correction of discretization error in molecular dynamics averages

The computation of statistical averages is one of the most important applications of molecular dynamics simulation, allowing for the estimation of macroscopic physical quantities through averages of observables sampled along microscopic trajectories. In this article, we investigate the impact of discretization error on the accuracy of molecular dynamics averages. Given a Hamiltonian system and a symplectic integrator, new weighting methods are derived to better approximate averages of certain observables, without changing the system or integrator. These new methods are shown to reduce discretization error and enhance the order of accuracy without high-overhead calculations.

How Processive Enzymes Work: the Application of Molecular Dynamics Simulation to Study the Catalytic Mechanism

How Processive Enzymes Work: the Application of Molecular Dynamics Simulation to Study the Catalytic Mechanism

Identification of Potential Small Molecule Binding Pockets on Rho Family GTPases

Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (>100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

Recent Progress in Molecular Dynamics Simulations of Dihydrofolate Reductase

This brief review will cover recent advances and applications of molecular dynamics simulations of dihydrofolate reductase over the course of the past few years. The application of the technique to the study of kinetic isotope effects, binding free energy of drugs, impact of ligand binding on protein conformation and study of coupled motions in hydrogen tunneling reactions will be discussed. Keywords: Molecular dynamics, dihydrofolate reductase, linear interaction energy, Generalized Born, Poisson-Boltzmann, HIV protease inhibitor, drug design, simulation, methotrexate, NADPH

DROPLET HEATING AND EVAPORATION−RECENT RESULTS AND UNSOLVED PROBLEMS

Recently developed approaches to the hydrodynamic, kinetic, and molecular dynamic modeling of fuel droplet heating and evaporation are reviewed. Two new solutions to the heat conduction equation, taking into account the effect of the moving boundary during transient heating of an evaporating droplet, are discussed. The first solution is the explicit analytical solution to this equation, while the second one reduces the solution of the differential transient heat conduction equation to the solution of the Volterra integral equation of the second kind. The new approach predicts lower droplet surface temperatures and slower evaporation rates compared with the traditional approach. An alternative approach to the same problem has been based on the assumption that the time evolution of a droplet's radius, Rd (t), is known. For sufficiently small time steps, the time evolutions of droplet surface temperatures and radii predicted by both approaches coincide. A simplified model for multi-component droplet heating and evaporation, based on the analytical solution to the species diffusion equation inside droplets, is discussed. Two new solutions to the equation, describing the diffusion of species during multi-component droplet evaporation taking into account the effects of the moving boundary, are presented. A quasi-discrete model for heating and evaporation of complex multi-component hydrocarbon fuel droplets is described. The predictions of the model, taking into account the effects of the moving boundary during the time steps on the solutions to the heat transfer and species diffusion equations, are discussed. A new algorithm, based on simple approximations of the kinetic results, suitable for engineering applications, is discussed. The results of kinetic modeling, taking into account the effects of inelastic collisions, and applications of molecular dynamics simulations to study the evaporation of n-dodecane droplets are briefly summarized. The most challenging and practically important unsolved problems with regard to the modeling of droplet heating and evaporation are summarized and discussed.

Exploring a Model of a Chemokine Receptor/Ligand Complex in an Explicit Membrane Environment by Molecular Dynamics Simulation: The Human CCR1 Receptor

The seven transmembrane helices G-protein-coupled receptors (GPCRs) form one of the largest superfamilies of signaling proteins found in humans. Homology modeling, molecular docking, and molecular dynamics (MD) simulation were carried out to construct a reliable model for CCR1 as one of the GPCRs and to explore the structural features and the binding mechanism of BX471 as one of the most potent CCR1 inhibitors. In this study, BX471 has been docked into the active site of the CCR1 protein. After docking, one 20 ns MD simulation was performed on the CCR1-ligand complex to explore effects of the presence of lipid membrane in the vicinity of the CCR1-ligand complex. At the end of the MD simulation, a change in the position and orientation of the ligand in the binding site was observed. This important observation indicated that the application of MD simulation after docking of ligands is useful. Explorative runs of molecular dynamics simulation on the receptor-ligand complex revealed that except for Phe85, Phe112, Tyr113, and Ile259, the rest of the residues in the active site determined by docking are changed. The results obtained are in good agreement with most of the experimental data reported by others. Our results show that molecular modeling and rational drug design for chemokine targets is a possible approach.

From agonist to antagonist: Structure and dynamics of innate immune glycoprotein MD-2 upon recognition of variably acylated bacterial endotoxins

The human immune response to an infection by Gram-negative bacteria involves detection of lipopolysaccharides (LPS), also known as endotoxins, which comprise the bacterial outer cell wall. Distinct from mammalian glycolipid structures, LPS have a conserved chemical pattern that is recognized by the pattern recognition receptor complex formed by myeloid differentiation protein 2 (MD-2) and toll-like receptor 4 (TLR4). A remarkable immune-mediated structure-toxicity relationship has been defined that relates to the number of acyl chains in the endotoxin. While there is a clear correlation between endotoxin acylation and elicited agonist or antagonist responses, the 3D structural basis of this relationship remains unclear. In order to explore, at atomic-resolution, the effects of a range of chemically distinct endotoxins on the structure and dynamics of their MD-2·endotoxin complexes, we examined a series of variably acylated lipid A molecules from Escherichia coli and Neisseria meningitidis in complex with human MD-2. Through the application of molecular dynamics simulations, in concert with experimental data, we have identified specific structural and dynamic features of the MD-2-endotoxin complexes that may control dimerization of TLR4 molecules. As dimerization is central to the release of downstream chemical mediators, the results provide a structural foundation for the ability of endotoxins to act as either agonists or antagonists of the TLR4 pathway.

Correction to Application of Molecular Dynamics Simulations in Molecular Property Prediction. 1. Density and Heat of Vaporization.

ADVERTISEMENT RETURN TO ISSUEPREVErratumORIGINAL ARTICLEThis notice is a correctionCorrection to Application of Molecular Dynamics Simulations in Molecular Property Prediction. 1. Density and Heat of VaporizationJunmei Wang* and Tingjun HouView Author InformationDepartment of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9050, United StatesInstitute of Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, P. R. ChinaCite this: J. Chem. Theory Comput. 2011, 7, 7, 2333Publication Date (Web):June 24, 2011Publication History Published online24 June 2011Published inissue 12 July 2011https://doi.org/10.1021/ct2004287Copyright © 2011 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views731Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (591 KB) Get e-Alerts Get e-Alerts

Application of Molecular Dynamics Simulations in Molecular Property Prediction. 1. Density and Heat of Vaporization

Molecular mechanical force field (FF) methods are useful in studying condensed phase properties. They are complementary to experiment and can often go beyond experiment in atomic details. Even a FF is specific for studying structures, dynamics and functions of biomolecules, it is still important for the FF to accurately reproduce the experimental liquid properties of small molecules that represent the chemical moieties of biomolecules. Otherwise, the force field may not describe the structures and energies of macromolecules in aqueous solutions properly. In this work, we have carried out a systematic study to evaluate the General AMBER Force Field (GAFF) in studying densities and heats of vaporization for a large set of organic molecules that covers the most common chemical functional groups. The latest techniques, such as the particle mesh Ewald (PME) for calculating electrostatic energies, and Langevin dynamics for scaling temperatures, have been applied in the molecular dynamics (MD) simulations. For density, the average percent error (APE) of 71 organic compounds is 4.43% when compared to the experimental values. More encouragingly, the APE drops to 3.43% after the exclusion of two outliers and four other compounds for which the experimental densities have been measured with pressures higher than 1.0 atm. For heat of vaporization, several protocols have been investigated and the best one, P4/ntt0, achieves an average unsigned error (AUE) and a root-mean-square error (RMSE) of 0.93 and 1.20 kcal/mol, respectively. How to reduce the prediction errors through proper van der Waals (vdW) parameterization has been discussed. An encouraging finding in vdW parameterization is that both densities and heats of vaporization approach their "ideal" values in a synchronous fashion when vdW parameters are tuned. The following hydration free energy calculation using thermodynamic integration further justifies the vdW refinement. We conclude that simple vdW parameterization can significantly reduce the prediction errors. We believe that GAFF can greatly improve its performance in predicting liquid properties of organic molecules after a systematic vdW parameterization, which will be reported in a separate paper.

Applications of molecular dynamics simulation in nonlinear optics

Organic nonlinear optical molecular materials have a number of important applications in frequency transformation, electrooptic modulation, two-photon absorption and so on. In this paper, we introduce the main applications of molecular dynamics simulation in theoretical study on nonlinear optical properties of organic molecules, including the electric field poling effects, the local field factors, the nonlinear susceptibilities, and the two-photon absorption. In addition, the important roles played by molecular dynamics simulation in the study of solvent and aggregation effects are also illustrated in combination with the recent research.

Conformational Flexibility in Designing Peptides for Immunology: The Molecular Dynamics Approach

Computational modeling techniques and computer simulations have become a routine in biological sciences and have gained great attention from researchers. Molecular dynamics simulation is a valuable tool towards an understanding of the complex structure of biological systems, especially in the study of the flexibility of the biological molecules such as peptides or proteins. Peptides play a very important role in human physiology and control many of the processes involved in the immune system response. Designing new and optimal peptide vaccines is one of the hottest challenges of the 21(st) century science and it brings together researchers from different fields. Molecular dynamics simulations have proven to be a helpful tool assisting laboratory work, saving financial sources and opening possibilities for exploring properties of the molecular systems that are hardly accessible by conventional experimental methods. Present review is dedicated to the recent contributions in applications of molecular dynamics simulations in peptide design for immunological purposes, such as B or T cell epitopes.

Molecular dynamics simulation of nanoscale liquid flows

Molecular dynamics (MD) simulation is a powerful tool to investigate the nanoscale fluid flow. In this article, we review the methods and the applications of MD simulation in liquid flows in nanochannels. For pressure-driven flows, we focus on the fundamental research and the rationality of the model hypotheses. For electrokinetic-driven flows and the thermal-driven flows, we concentrate on the principle of generating liquid motion. The slip boundary condition is one of the marked differences between the macro- and micro-scale flows and the nanoscale flows. In this article, we review the parameters controlling the degree of boundary slip and the new findings. MD simulation is based on the Newton's second law to simulate the particles' interactions and consists of several important processing methods, such as the thermal wall model, the cut-off radius, and the initial condition. Therefore, we also reviewed the recent improvement in these key methods to make the MD simulation more rational and efficient. Finally, we summarized the important discoveries in this research field and proposed some worthwhile future research directions.

On the catalytic role of structural fluctuations in enzyme reactions: computational evidence on the formation of compound 0 in horseradish peroxidase

In this study the question as to whether and to what extent horseradish peroxidase (HRP) enzyme structural flexibility affects the free energy barrier for the formation of the key intermediate compound 0 (Cpd0) is addressed by the use of a combined application of molecular dynamics simulations and perturbed matrix method calculations. Results are intriguing and indicate that, within the simulated conditions, free energy profiles are substantially affected by structural fluctuations of the whole surrounding biological environment (i.e. HRP enzyme and solvent). In this respect our results show that the combined effect of enzyme and solvent provides a substantial lowering of the free energy barrier to the formation of Cpd0, with respect to both gas-phase and QM/MM results carried out at a comparable level of theory. A careful inspection of such observations and their general implications in currently employed methodological approaches to the modelling of enzyme reactions, is also discussed.

High-Performance Drug Discovery: Computational Screening by Combining Docking and Molecular Dynamics Simulations

Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our screening approach employed the molecular mechanics/Poisson-Boltzmann and surface area method to estimate the binding free energies. For the top-ranking 1,000 compounds obtained by docking to a target protein, approximately 6,000 molecular dynamics simulations were performed using multiple docking poses in about a week. As a result, the enrichment performance of the top 100 compounds by our approach was improved by 1.6–4.0 times that of the enrichment performance of molecular dockings. This result indicates that the application of molecular dynamics simulations to virtual screening for lead discovery is both effective and practical. However, further optimization of the computational protocols is required for screening various target proteins.

Computational and Experimental Analyses Converge to Reveal a Coherent Yet Malleable Aptamer Structure That Controls Chemical Reactivity

As short nucleic acids, aptamers in solution are believed to be structurally flexible. Consistent with this view, most aptamers examined for this property have been shown to bind their target molecules by mechanisms that can be described as "induced fit". But, it is not known to what extent this structural flexibility affects the integrity of the target-aptamer interaction. Using the malachite green aptamer (MGA) as a model system, we show that the MGA can protect its bound target, malachite green (MG), from oxidation over several days. Protection is reversed by an oligonucleotide complementary to the MGA binding pocket. Computational cavity analysis of the MGA-MG structure predicted that MG oxidation is protected because a molecule as small as an OH(-) is sterically excluded from the C1 position of the bound MG. These results suggest that, while the MGA-MG interface is sufficiently coherent to prevent OH(-) penetration, the bases involved in the interaction are sufficiently mobile that they can exchange out of the MG binding interface to hybridize with a complementary oligonucleotide. The computational predictions were confirmed experimentally using variants of the MGA with single base changes in the binding pocket. This work demonstrates the successful application of molecular dynamics simulations and cavity analysis in determining the effects of sequence variations on the structure of a small single-stranded nucleic acid. It also shows that a nucleic acid aptamer can control access to specific chemical groups on its target, which suggests that aptamers might be applied for selectively protecting small molecules from modification.

Molecular dynamics simulations on the critical states of the farnesyltransferase enzyme

Protein farnesyltransferase (FTase) is a particularly interesting zinc enzyme that promotes the transfer of a 15-carbons isoprenoid farnesyl group from farnesyl diphosphate (FPP) to a number of peptide substrates with a typical-CAAX motif at the carboxyl-terminus, where C represents the cysteine residue that is farnesylated. This enzyme has been the subject of great attention in anticancer research, as several proteins known to be involved in human cancer development are thought to serve as substrates for FTase and to require farnesylation for proper biological activity. Several FTase inhibitors have advanced into clinical testing. However, despite the progress in the field several functional and mechanistic doubts on the FTase catalytic activity have persisted. This work describes the application of molecular dynamics simulations using specifically designed molecular mechanical parameters to the four key-intermediate states formed during the FTase catalytic mechanism–FTase resting state, binary complex (FTase-FPP), ternary complex (FTase-FPP-Peptide), and product complex (FTase-Product). The study involves a comparative analysis of several important molecular aspects for which are vital not only motion but also the conformational sampling of both enzyme and substrate as well as their interaction, and especially the effect of the solvent. These include the radial distribution function of the water molecules around the catalytically important zinc metal atom, the conformations of the substrate and product molecules and the corresponding RMSF values, critical hydrogen bonds and several catalytically relevant distances. These results are discussed in light of recent experimental and computational evidence, yielding new insights into the elusive catalytic mechanism of this enzyme.