Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Enhanced Conformational Sampling Using Replica Exchange with Collective-Variable Tempering.

ABSTRACT: The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strengths of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. The method is tested on alanine dipeptide and applied to the difficult problem of conformational sampling in a tetranucleotide.

SUBMITTER: Gil-Ley A

PROVIDER: S-EPMC4364913 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Enhanced Conformational Sampling Using Replica Exchange with Collective-Variable Tempering.

Gil-Ley Alejandro A Bussi Giovanni G

Journal of chemical theory and computation 20150301 3

The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strengths of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are sig ...[more]

PMID: 25838811

Similar Datasets

Enhanced Conformational Sampling of Nanobody CDR H3 Loop by Generalized Replica-Exchange with Solute Tempering.

Project description:The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, we investigate the applicability of an enhanced sampling method, a generalized replica-exchange with solute tempering (gREST) for sampling CDR-H3 loop structures of nanobodies. In the conventional replica-exchange methods, temperatures of only a whole system or scaling parameters of a solute molecule are selected for temperature or parameter exchange. In gREST, we can flexibly select a part of a solute molecule and a part of the potential energy terms as a parameter exchange region. We selected the CDR-H3 loop and investigated which potential energy term should be selected for the efficient sampling of the loop structures. We found that the gREST with dihedral terms can explore a global conformational space, but the relaxation to the global equilibrium is slow. On the other hand, gREST with all the potential energy terms can sample the equilibrium distribution, but the structural exploration is slower than with dihedral terms. The lessons learned from this study can be applied to future studies of loop modeling.

| S-EPMC8706460 | biostudies-literature

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering.

Project description:With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein-ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site.

| S-EPMC3985685 | biostudies-other

Enhanced Sampling of Buried Charges in Free Energy Calculations Using Replica Exchange with Charge Tempering.

Project description:Buried ionizable groups in proteins often play important structural and functional roles. However, it is generally challenging to study the detailed molecular mechanisms solely based on experimental measurements. Free energy calculations using atomistic simulations, on the other hand, complement experimental studies and can provide high temporal and spatial resolution information that can lead to mechanistic insights. Nevertheless, it is also well recognized that sufficient sampling of such atomistic simulations can be challenging, considering that structural changes related to the buried charges may be very slow. In the present study, we describe a simple but effective enhanced sampling technique called replica exchange with charge tempering (REChgT) with a novel free energy method, multisite λ dynamics (MSλD), to study two systems containing buried charges, pKa prediction of a small molecule, orotate, in complex with the dihydroorotate dehydrogenase, and relative stability of a Glu-Lys pair buried in the hydrophobic core of two variants of Staphylococcal nuclease. Compared to the original MSλD simulations, the usage of REChgT dramatically increases sampling in both conformational and alchemical spaces, which directly translates into a significant reduction of wall time to converge the free energy calculations. This study highlights the importance of sufficient sampling toward developing improved free energy methods.

| S-EPMC11275198 | biostudies-literature

Enhanced conformational sampling using replica exchange with concurrent solute scaling and hamiltonian biasing realized in one dimension.

Project description:Replica exchange (REX) is a powerful computational tool for overcoming the quasi-ergodic sampling problem of complex molecular systems. Recently, several multidimensional extensions of this method have been developed to realize exchanges in both temperature and biasing potential space or the use of multiple biasing potentials to improve sampling efficiency. However, increased computational cost due to the multidimensionality of exchanges becomes challenging for use on complex systems under explicit solvent conditions. In this study, we develop a one-dimensional (1D) REX algorithm to concurrently combine the advantages of overall enhanced sampling from Hamiltonian solute scaling and the specific enhancement of collective variables using Hamiltonian biasing potentials. In the present Hamiltonian replica exchange method, termed HREST-BP, Hamiltonian solute scaling is applied to the solute subsystem, and its interactions with the environment to enhance overall conformational transitions and biasing potentials are added along selected collective variables associated with specific conformational transitions, thereby balancing the sampling of different hierarchical degrees of freedom. The two enhanced sampling approaches are implemented concurrently allowing for the use of a small number of replicas (e.g., 6 to 8) in 1D, thus greatly reducing the computational cost in complex system simulations. The present method is applied to conformational sampling of two nitrogen-linked glycans (N-glycans) found on the HIV gp120 envelope protein. Considering the general importance of the conformational sampling problem, HREST-BP represents an efficient procedure for the study of complex saccharides, and, more generally, the method is anticipated to be of general utility for the conformational sampling in a wide range of macromolecular systems.

| S-EPMC4463548 | biostudies-literature

Replica exchange with solute scaling: a more efficient version of replica exchange with solute tempering (REST2).

Project description:A small change in the Hamiltonian scaling in Replica Exchange with Solute Tempering (REST) is found to improve its sampling efficiency greatly, especially for the sampling of aqueous protein solutions in which there are large-scale solute conformation changes. Like the original REST (REST1), the new version (which we call REST2) also bypasses the poor scaling with system size of the standard Temperature Replica Exchange Method (TREM), reducing the number of replicas (parallel processes) from what must be used in TREM. This reduction is accomplished by deforming the Hamiltonian function for each replica in such a way that the acceptance probability for the exchange of replica configurations does not depend on the number of explicit water molecules in the system. For proof of concept, REST2 is compared with TREM and with REST1 for the folding of the trpcage and β-hairpin in water. The comparisons confirm that REST2 greatly reduces the number of CPUs required by regular replica exchange and greatly increases the sampling efficiency over REST1. This method reduces the CPU time required for calculating thermodynamic averages and for the ab initio folding of proteins in explicit water.

| S-EPMC3172817 | biostudies-literature

Replica exchange with solute tempering: efficiency in large scale systems.

Project description:We apply the recently developed replica exchange with solute tempering (REST) to three large solvated peptide systems: an alpha-helix, a beta-hairpin, and a TrpCage, with these peptides defined as the "central group". We find that our original implementation of REST is not always more efficient than the replica exchange method (REM). Specifically, we find that exchanges between folded (F) and unfolded (U) conformations with vastly different structural energies are greatly reduced by the nonappearance of the water self-interaction energy in the replica exchange acceptance probabilities. REST, however, is expected to remain useful for a large class of systems for which the energy gap between the two states is not large, such as weakly bound protein-ligand complexes. Alternatively, a shell of water molecules can be incorporated into the central group, as discussed in the original paper.

| S-EPMC2744475 | biostudies-literature

Acceleration of Lateral Equilibration in Mixed Lipid Bilayers Using Replica Exchange with Solute Tempering.

Project description:The lateral heterogeneity of cellular membranes plays an important role in many biological functions such as signaling and regulating membrane proteins. This heterogeneity can result from preferential interactions between membrane components or interactions with membrane proteins. One major difficulty in molecular dynamics simulations aimed at studying the membrane heterogeneity is that lipids diffuse slowly and collectively in bilayers, and therefore, it is difficult to reach equilibrium in lateral organization in bilayer mixtures. Here, we propose the use of the replica exchange with solute tempering (REST) approach to accelerate lateral relaxation in heterogeneous bilayers. REST is based on the replica exchange method but tempers only the solute, leaving the temperature of the solvent fixed. Since the number of replicas in REST scales approximately only with the degrees of freedom in the solute, REST enables us to enhance the configuration sampling of lipid bilayers with fewer replicas, in comparison with the temperature replica exchange molecular dynamics simulation (T-REMD) where the number of replicas scales with the degrees of freedom of the entire system. We apply the REST method to a cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer mixture and find that the lateral distribution functions of all molecular pair types converge much faster than in the standard MD simulation. The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation. Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.

| S-EPMC4196747 | biostudies-literature

Conformational Ensembles of ?-Synuclein Derived Peptide with Different Osmolytes from Temperature Replica Exchange Sampling.

Project description:Intrinsically disordered proteins (IDP) are a class of proteins that do not have a stable three-dimensional structure and can adopt a range of conformations playing various vital functional role. Alpha-synuclein is one such IDP which can aggregate into toxic protofibrils and has been associated largely with Parkinson's disease (PD) along with other neurodegenerative diseases. Osmolytes are small organic compounds that can alter the environment around the proteins by acting as denaturants or protectants for the proteins. In the present study, we have conducted a series of replica exchange molecular dynamics simulations to explore the role of osmolytes, urea which is a denaturant and TMAO (trimethylamine N-oxide), a protecting osmolyte, in aggregation and conformations of the synuclein peptide. We observed that both the osmolytes have significantly distinct impacts on the peptide and led to transitions of the conformations of the peptide from one state to other. Our findings highlighted that urea attenuated peptide aggregation and resulted in the formation of extended peptide structures whereas TMAO led to compact and folded forms of the peptide.

| S-EPMC5725442 | biostudies-literature

Using the multi-objective optimization replica exchange Monte Carlo enhanced sampling method for protein-small molecule docking.

Project description:BackgroundIn this study, we extended the replica exchange Monte Carlo (REMC) sampling method to protein-small molecule docking conformational prediction using RosettaLigand. In contrast to the traditional Monte Carlo (MC) and REMC sampling methods, these methods use multi-objective optimization Pareto front information to facilitate the selection of replicas for exchange.ResultsThe Pareto front information generated to select lower energy conformations as representative conformation structure replicas can facilitate the convergence of the available conformational space, including available near-native structures. Furthermore, our approach directly provides min-min scenario Pareto optimal solutions, as well as a hybrid of the min-min and max-min scenario Pareto optimal solutions with lower energy conformations for use as structure templates in the REMC sampling method. These methods were validated based on a thorough analysis of a benchmark data set containing 16 benchmark test cases. An in-depth comparison between MC, REMC, multi-objective optimization-REMC (MO-REMC), and hybrid MO-REMC (HMO-REMC) sampling methods was performed to illustrate the differences between the four conformational search strategies.ConclusionsOur findings demonstrate that the MO-REMC and HMO-REMC conformational sampling methods are powerful approaches for obtaining protein-small molecule docking conformational predictions based on the binding energy of complexes in RosettaLigand.

| S-EPMC5504647 | biostudies-literature

Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Free Energy Calculation.

Project description:Through adding a harmonic boost potential to smooth the system potential energy surface, Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and free energy calculation of biomolecules without the need of predefined reaction coordinates. This work continues to improve the acceleration power and energy reweighting of the GaMD by combining the GaMD with replica exchange algorithms. Two versions of replica exchange GaMD (rex-GaMD) are presented: force constant rex-GaMD and threshold energy rex-GaMD. During simulations of force constant rex-GaMD, the boost potential can be exchanged between replicas of different harmonic force constants with fixed threshold energy. However, the algorithm of threshold energy rex-GaMD tends to switch the threshold energy between lower and upper bounds for generating different levels of boost potential. Testing simulations on three model systems, including the alanine dipeptide, chignolin, and HIV protease, demonstrate that through continuous exchanges of the boost potential, the rex-GaMD simulations not only enhance the conformational transitions of the systems but also narrow down the distribution width of the applied boost potential for accurate energetic reweighting to recover biomolecular free energy profiles.

| S-EPMC6747702 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data