Replica Exchange Molecular Dynamics Method Research Articles

Rapid Rescoring and Refinement of Ligand-Receptor Complexes Using Replica Exchange Molecular Dynamics with a Monte Carlo Pose Reservoir.

Virtual screening (VS) involves generation of poses for a library of ligands and ranking using simplified energy functions and limited flexibility. Top-scored poses are used to rank and prioritize ligands. Here, we adapt the reservoir replica exchange molecular dynamics (res-REMD) method to rerank poses generated through VS. REMD simulations are carried out but with occasional Monte Carlo jumps to alternate VS-generated poses using a Metropolis criterion. The simulations converge within 10 ns for all systems, generating populations of alternate poses in the context of fully flexible ligand and protein side chains. The protocol is applied to four model protein-ligand complexes, where DOCK resulted in two successes and two scoring failures. In all four systems, the most populated cluster from the final ensemble exhibits high similarity to the crystallographic pose with ligand RMSD values under 2.0 Å. Both DOCK failures were rescued. For one DOCK success, the protocol identified the correct pose but also sampled an alternate pose at equal probability. Opportunities for future improvements and extensions are discussed.

Acceleration of generalized replica exchange with solute tempering simulations of large biological systems on massively parallel supercomputer.

Generalized replica exchange with solute tempering (gREST) is one of the enhanced sampling algorithms for proteins or other systems with rugged energy landscapes. Unlike the replica-exchange molecular dynamics (REMD) method, solvent temperatures are the same in all replicas, while solute temperatures are different and are exchanged frequently between replicas for exploring various solute structures. Here, we apply the gREST scheme to large biological systems containing over one million atoms using a large number of processors in a supercomputer. First, communication time on a multi-dimensional torus network is reduced by matching each replica to MPI processors optimally. This is applicable not only to gREST but also to other multi-copy algorithms. Second, energy evaluations, which are necessary for the multistate bennet acceptance ratio (MBAR) method for free energy estimations, are performed on-the-fly during the gREST simulations. Using these two advanced schemes, we observed 57.72 ns/day performance in 128-replica gREST calculations with 1.5 million atoms system using 16,384 nodes in Fugaku. These schemes implemented in the latest version of GENESIS software could open new possibilities to answer unresolved questions on large biomolecular complex systems with slow conformational dynamics.

Repulsive Scaling Replica Exchange Molecular Dynamics in Modeling Protein-Glycosaminoglycan Complexes.

Glycosaminoglycans are long linear periodic anionic polysaccharides consisting of disaccharide units exhibiting different sulfation patterns forming a highly heterogeneous group of molecules. Due to their flexibility, length, high charge, and periodicity, they are challenging for computational approaches. Despite their biological significance in terms of the important role in various diseases (e.g., Alzheimer, cancer, SARS-CoV-2) and proper cell functioning (e.g., proliferation, maturation), there is a lack of effective molecular docking tools designed specifically for glycosaminoglycans due to their challenging physical-chemical nature. In this chapter we present protocols for the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) methods to dock glycosaminoglycans withboth implicit and explicit solvent models implemented. This novel molecular dynamics-based replica exchange technique should help to elevate our current knowledge on the complexes and interactions between glycosaminoglycans and their protein receptors.

Investigating the folding mechanism of the N-terminal domain of ribosomal protein L9.

Protein folding is a popular topic in the life science. However, due to the limited sampling ability of experiments and simulations, the general folding mechanism is not yet clear to us. In this work, we study the folding of the N-terminal domain of ribosomal protein L9 (NTL9) in detail by a mixing replica exchange molecular dynamics method. The simulation results are close to previous experimental observations. According to the Markov state model, the folding of the protein follows a nucleation-condensation path. Moreover, after the comparison to its 39-residue β-α-β motif, we find that the helix at the C-terminal has a great influence on the folding process of the intact protein, including the nucleation of the key residues in the transition state ensemble and the packing of the hydrophobic residues in the native state.

Heteroaryldihydropyrimidines Alter Capsid Assembly By Adjusting the Binding Affinity and Pattern of the Hepatitis B Virus Core Protein.

Hepatitis B virus (HBV) infections are a major global health concern, for which heteroaryldihydropyrimidines (HAPs) have been developed. HAPs accelerate and/or result in aberrant capsid assembly; however, their effect on the assembly mechanism is unknown. This study aimed to compare the effects of three representative HAPs on core protein dimer assembly through molecular dynamics simulations and free energy calculations. Molecular docking and equilibrium simulations showed that different HAPs bind at the same binding site and are involved in different interactions. The observed conformational changes in HAPs deter the calculation of binding affinity. Herein, the reduced free energy perturbation/Hamiltonian replica exchange molecular dynamics method was used to enhance sampling during binding affinity calculations, indicating consistency between the binding free energies of HAPs and pEC50. Furthermore, binding pattern analysis revealed that the tetramer could sample flat structures after binding HAPs. The present results suggest a mechanism wherein HAPs accelerate capsid assembly by increasing the binding affinity of dimers, leading to aberrant assembly by altering the binding orientation of dimers.

FSATOOL: A useful tool to do the conformational sampling and trajectory analysis work for biomolecules.

Reliable conformational sampling and trajectory analysis are always important to the study of the folding or binding mechanisms of biomolecules. Generally, one has to prepare many complicated parameters and follow a lot of steps to obtain the final data. The whole process is too complicated to new users. In this article, we provide a convenient and user-friendly tool that is compatible to AMBER, called fast sampling and analysis tool (FSATOOL). FSATOOL has some useful features. First and the most important, the whole work is extremely simplified into two steps, one is the fast sampling procedure and the other is the trajectory analysis procedure. Second, it contains several powerful sampling methods for the simulation on graphics process unit, including our previous mixing replica exchange molecular dynamics method. The method combines the advantages of the biased and unbiased simulations. Finally, it extracts the dominant transition pathways automatically from the folding network by Markov state model. Users do not need to do the tedious intermediate steps by hand. To illustrate the usage of FSATOOL in practice, we perform one simulation for a RNA hairpin in explicit solvent. All the results are presented. © 2019 Wiley Periodicals, Inc.

A two-dimensional replica-exchange molecular dynamics method for simulating RNA folding using sparse experimental restraints.

We present a 2D replica exchange protocol incorporating secondary structure information to dramatically improve 3D RNA folding using molecular dynamics simulations. We show that incorporating base-pairing restraints into all-atom, explicit solvent simulations enables the accurate recapitulation of the global tertiary fold for 4 representative RNAs ranging in length from 24 to 68 nt. This method can potentially utilize base-pairing information from a wide variety of experimental inputs to predict complex RNA tertiary folds including pseudoknots, multi-loop junctions, and non-canonical interactions.

Structural Analysis of a Trimer of β2-Microgloblin Fragment by Molecular Dynamics Simulations

A peptide β2-m21−31, which is a fragment from residue 21 to residue 31 of β2-microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to understand the mechanism of amyloid fibril formations, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of β2-m21−31. From the analyses on the temperature dependence, we found that there is a clear phase transition temperature in which the peptides aggregate with each other. Moreover, we found by the free energy analyses that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates.

Replica-Exchange Methods for Biomolecular Simulations.

In this study, a replica-exchange method was developed to overcome conformational sampling difficulties in computer simulations of spin glass or other systems with rugged free-energy landscapes. This method was then applied to the protein-folding problem in combination with molecular dynamics (MD) simulation. Owing to its simplicity and sampling efficiency, the replica-exchange method has been applied to many other biological problems and has been continuously improved. The method has often been combined with other sampling techniques, such as umbrella sampling, free-energy perturbation, metadynamics, and Gaussian accelerated MD (GaMD). In this chapter, we first summarize the original replica-exchange molecular dynamics (REMD) method and discuss how new algorithms related to the original method are implemented to add new features. Heterogeneous and flexible structures of an N-glycan in a solution are simulated as an example of applications by REMD, replica exchange with solute tempering, and GaMD. The sampling efficiency of these methods on the N-glycan system and the convergence of the free-energy changes are compared. REMD simulation protocols and trajectory analysis using the GENESIS software are provided to facilitate the practical use of advanced simulation methods.

Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis.

Replica-exchange molecular dynamics (REMD) has been proven to efficiently improve the convergence of free-energy perturbation (FEP) calculations involving considerable reorganization of their surrounding. We previously introduced the FEP/(λ,H)-REMD algorithm for ligand binding, in which replicas along the alchemical thermodynamic coupling axis λ were expanded as a series of Hamiltonian boosted replicas along a second axis to form a two-dimensional replica-exchange exchange map [Jiang, W.; Roux, B., J. Chem. Theory Comput. 2010, 6 (9), 2559-2565]. Aiming to achieve a similar performance at a lower computational cost, we propose here a modified version of this algorithm in which only the end-states along the alchemical axis are augmented by boosted replicas. The reduced FEP/(λ,H)-REMD method with one-dimensional unbiased alchemical thermodynamic coupling axis λ is implemented on the basis of generic multiple copy algorithm (MCA) module of the biomolecular simulation program NAMD. The flexible MCA framework of NAMD enables a user to design customized replica-exchange patterns through Tcl scripting in the context of a highly parallelized simulation program without touching the source code. Two Hamiltonian tempering boosting scheme were examined with the new algorithm: a first one based on potential energy rescaling of a preidentified "solute" and a second one via the introduction of flattening torsional free-energy barriers. As two illustrative examples with reliable experiment data, the absolute binding free energies of p-xylene and n-butylbenzene to the nonpolar cavity of the L99A mutant of T4 lysozyme were calculated. The tests demonstrate that the new protocol efficiently enhances the sampling of torsional motions for backbone and side chains around the binding pocket and accelerates the convergence of the free-energy computations.

Replica-Based Protein Structure Sampling Methods: Compromising between Explicit and Implicit Solvents.

The structure of a protein is often not completely accessible by experiments. In silico, replica exchange molecular dynamics (REMD) is the standard sampling method for predicting the secondary and tertiary structures from the amino acid sequence, but it is computationally very expensive. Two recent adaptations from REMD, temperature intervals with global exchange of replicas (TIGER2) and TIGER2A, have been tested here in implicit and explicit solvents. Additionally, explicit, implicit, and hybrid solvent REMD are compared. On the basis of the hybrid REMD (REMDh) method, we present a new hybrid TIGER2h algorithm for faster structural sampling, while retaining good accuracy. The implementations of REMDh, TIGER2, TIGER2A, and TIGER2h are provided for nanoscale molecular dynamics (NAMD). All the methods were tested with two model peptides of known structure, (AAQAA)3 and HP7, with helix and sheet motifs, respectively. The TIGER2 methods and REMDh were also applied to the unknown structure of the collagen type I telopeptides, which represent bigger proteins with some degree of disorder. We present simulations covering more than 180 μs and analyze the performance and convergence of the distributions of states between the particular methods by dihedral principal component and secondary structure analysis.

Flexible Choice of Solute in Replica Exchange with Solute Tempering Can Improve Performance of Conformation Search for Small Proteins

Replica exchange with solute tempering (REST) significantly reduces computational cost in comparison with conventional temperature replica exchange molecular dynamics method. We extended the solute selection scheme of this REST, to avoid parameter space trapping problem and associated loss in conformational search efficiencies happen in REST. The new scheme, which we call generalized REST (gREST), accepts energy term based partitioning in addition to the particle based one; the solute region can involve only dihedral energy terms, for example. We applied this gREST to the folding and free energy landscape calculations of Trp-cage small protein system, where only dihedral energy terms were considered as the solute (dihedral-gREST), and compared its efficiency with the most frequently used REST variant, REST2. Using this dihedral-gREST, we successfully found the native state of Trp-cage in comparable timescale as REST2 with almost a half of computational cost. Moreover, the free energy landscape, calculated with multistate Bennett acceptance ratio (MBAR), of REST2 underestimated the stability of unfolded state and the convergence rate of the free energy map was slower than that by dihedral-gREST. In REST2, stable structures including the native one favor states with smaller energy scaling coefficients (lower REST temperature, in other words), which is caused by the disturbance in solute and solvent energy compensations due to the energy scaling coefficients. This trapping in the parameter space eventually resulted in the less accurate free energy map. In contrast, dihedral-gREST did not suffer from such a trapping in the parameter space. This generalized variant of REST, gREST, can further extend the capability of REST scheme and is expected to improve many types of simulations including free energy calculations.

Replica Exchange Molecular Dynamics: A Practical Application Protocol with Solutions to Common Problems and a Peptide Aggregation and Self-Assembly Example.

Protein aggregation is associated with many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and type II diabetes (T2D). Understanding the molecular mechanism of protein aggregation is essential for therapy development. Molecular dynamics (MD) simulations have been shown as powerful tools to study protein aggregation. However, conventional MD simulations can hardly sample the whole conformational space of complex protein systems within acceptable simulation time as it can be easily trapped in local minimum-energy states. Many enhanced sampling methods have been developed. Among these, the replica exchange molecular dynamics (REMD) method has gained great popularity. By combining MD simulation with the Monte Carlo algorithm, the REMD method is capable of overcoming high energy-barriers easily and of sampling sufficiently the conformational space of proteins. In this chapter, we present a brief introduction to REMD method and a practical application protocol with a case study of the dimerization of the 11-25 fragment of human islet amyloid polypeptide (hIAPP(11-25)), using the GROMACS software. We also provide solutions to problems that are often encountered in practical use, and provide some useful scripts/commands from our research that can be easily adapted to other systems.

Influence of various parameters in the replica-exchange molecular dynamics method: Number of replicas, replica-exchange frequency, and thermostat coupling time constant.

The replica-exchange molecular dynamics (REMD) method has been used for conformational sampling of various biomolecular systems. To maximize sampling efficiency, some adjustable parameters must be optimized. Although it is agreed that shorter intervals between the replica-exchange attempts enhance traversals in the temperature space, details regarding the artifacts caused by these short intervals are controversial. In this study, we revisit this problem by performing REMD simulations on an alanine octapeptide in an implicit solvent. Fifty different sets of conditions, which are a combination of five replica-exchange periods, five different numbers of replicas, and two thermostat coupling time constants, were investigated. As a result, although short replica-exchange intervals enhanced the traversals in the temperature space, they led to artifacts in the ensemble average of the temperature, potential energy, and helix content. With extremely short replica-exchange intervals, i.e., attempted at every time step, the ensemble average of the temperature deviated from the thermostat temperature by ca. 7 K. Differences in the ensembles were observed even for larger replica-exchange intervals (between 100 and 1,000 steps). In addition, the shorter thermostat coupling time constant reduced the artifacts found when short replica-exchange intervals were used, implying that these artifacts are caused by insufficient thermal relaxation between the replica-exchange events. Our results will be useful to reduce the artifacts found in REMD simulations by adjusting some key parameters.

Two major stable structures of amyloid-forming peptides: amorphous aggregates and amyloid fibrils

A peptide -m, which is a fragment from residue 21 to residue 31 of -microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to analyze the conformations of amyloid-forming peptides in the early stage of aggregation, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of -m. From the analyses concerned with the temperature dependence, we found that there is a clear transition temperature in which the peptides aggregate each other. Moreover, we found that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates by the free energy analyses.

General Formalism of Mass Scaling Approach for Replica-Exchange Molecular Dynamics and its Application

Replica-exchange molecular dynamics (REMD) has demonstrated its efficiency by combining trajectories of a wide range of temperatures. As an extension of the method, the author formalizes the mass-manipulating replica-exchange molecular dynamics (MMREMD) method that allows for arbitrary mass scaling with respect to temperature and individual particles. The formalism enables the versatile application of mass-scaling approaches to the REMD method. The key change introduced in the novel formalism is the generalized rules for the velocity and momentum scaling after accepted replica-exchange attempts. As an application of this general formalism, the refinement of the viscosity-REMD (V-REMD) method [P. H. Nguyen, J. Chem. Phys. 132, 144109 (2010)] is presented. Numerical results are provided using a pilot system, demonstrating easier and more optimized applicability of the new version of V-REMD as well as the importance of adherence to the generalized velocity scaling rules. With the new formalism, more sound an...

From cellulose to kerogen: molecular simulation of a geological process.

The process by which organic matter decomposes deep underground to form petroleum and its underlying kerogen matrix has so far remained a no man's land to theoreticians, largely because of the geological (Myears) timescale associated with the process. Using reactive molecular dynamics and an accelerated simulation framework, the replica exchange molecular dynamics method, we simulate the full transformation of cellulose into kerogen and its associated fluid phase under prevailing geological conditions. We observe in sequence the fragmentation of the cellulose crystal and production of water, the development of an unsaturated aliphatic macromolecular phase and its aromatization. The composition of the solid residue along the maturation pathway strictly follows what is observed for natural type III kerogen and for artificially matured samples under confined conditions. After expulsion of the fluid phase, the obtained microporous kerogen possesses the structure, texture, density, porosity and stiffness observed for mature type III kerogen and a microporous carbon obtained by saccharose pyrolysis at low temperature. As expected for this variety of precursor, the main resulting hydrocarbon is methane. The present work thus demonstrates that molecular simulations can now be used to assess, almost quantitatively, such complex chemical processes as petrogenesis in fossil reservoirs and, more generally, the possible conversion of any natural product into bio-sourced materials and/or fuel.

An Active Site Opening Mechanism in a (Pyridylamide)hafnium(IV) Ion Pair Catalyst: An Associative Mechanism

We report a molecular dynamics (MD) study on the ion pair [{N–,N,C–}HfMe][MeB(C6F5)3], which is the active species of a (pyridylamide)hafnium(IV) complex for olefin polymerization. The present simulation model system is composed of an ion pair in explicit organic solvent (heptane) with and without ethylene monomers. MD simulations revealed an active site opening (ASO) mechanism, i.e., the associative active site opening (AASO), where the counteranion dissociates from the active site associatively with the monomer coordination to the active site. AASO also explains consistently the experimental fact that the activity of the catalyst increases when the counteranion has no Me groups. Further we show that AASO is the major mechanism of ASO by using the replica exchange molecular dynamics (REMD) method. In addition, we discuss two important factors for the AASO: one is the structural condition of the ion pair, and the other is the net stabilization energy. Finally, we conclude that both the ASO and the monomer coordination should be taken into account to accurately design the behavior of the ion pair and predict the activity.

Anharmonic Vibrational Analyses of Pentapeptide Conformations Explored with Enhanced Sampling Simulations.

An accurate theoretical prediction of the vibrational spectrum of polypeptides remains to be a challenge due to (1) their conformational flexibility and (2) non-negligible anharmonic effects. The former makes the search for conformers that contribute to the spectrum difficult, and the latter requires an expensive, quantum mechanical calculation for both electrons and vibrations. Here, we propose a new theoretical approach, which implements an enhanced conformational sampling by the replica-exchange molecular dynamics method, a structural clustering to identify distinct conformations, and a vibrational structure calculation by the second-order vibrational quasi-degenerate perturbation theory (VQDPT2). A systematic mode-selection scheme is developed to reduce the cost of VQDPT2 and the generation of a potential energy surface by the electronic structure calculation. The proposed method is applied to a pentapeptide, SIVSF-NH2, for which the infrared spectrum has recently been measured in the gas phase with high resolution in the OH and NH stretching region. The theoretical spectrum of the lowest energy conformer is obtained with a mean absolute deviation of 11.2 cm-1 from the experimental spectrum. Furthermore, the NH stretching frequencies of the five lowest energy conformers are found to be consistent with the literature values measured for small peptides with a similar secondary structure. Therefore, the proposed method is a promising way to analyze the vibrational spectrum of polypeptides.

Walking freely in the energy and temperature space by the modified replica exchange molecular dynamics method.

Replica Exchange Molecular Dynamics (REMD) method is a powerful sampling tool in molecular simulations. Recently, we made a modification to the standard REMD method. It places some inactive replicas at different temperatures as well as the active replicas. The method completely decouples the number of the active replicas and the number of the temperature levels. In this article, we make a further modification to our previous method. It uses the inactive replicas in a different way. The inactive replicas first sample in their own knowledge-based energy databases and then participate in the replica exchange operations in the REMD simulation. In fact, this method is a hybrid between the standard REMD method and the simulated tempering method. Using different active replicas, one can freely control the calculation quantity and the convergence speed of the simulation. To illustrate the performance of the method, we apply it to some small models. The distribution functions of the replicas in the energy space and temperature space show that the modified REMD method in this work can let the replicas walk freely in both of the two spaces. With the same number of the active replicas, the free energy surface in the simulation converges faster than the standard REMD. © 2016 Wiley Periodicals, Inc.