Replica Exchange With Solute Tempering Research Articles

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-β-Sheet Transition and Conformational Shift.

The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is associated with amyotrophic lateral sclerosis (ALS). The 311-360 fragment of TDP-43 (TDP-43311-360), the amyloidogenic core region, can spontaneously aggregate into fibrils, and the ALS-associated mutation G335D has an enhanced effect on TDP-43311-360 fibrillization. However, the molecular mechanism underlying G335D-enhanced aggregation at atomic level remains largely unknown. By utilizing all-atom molecular dynamics (MD) and replica exchange with solute tempering 2 (REST2) simulations, we investigated influences of G335D on the dimerization (the first step of aggregation) and conformational ensemble of the TDP-43311-360 peptide. Our simulations show that G335D mutation increases inter-peptide interactions, especially inter-peptide hydrogen-bonding interactions in which the mutant site has a relatively large contribution, and enhances the dimerization of TDP-43311-360 peptides. The α-helix regions in the NMR-resolved conformation of the TDP-43311-360 monomer (321-330 and 335-343) play an essential role in the formation of the dimer. G335D mutation induces helix unfolding and promotes α-to-β conversion. G335D mutation alters the conformational distribution of TDP-43311-360 dimers and causes population shift from helix-rich to β-sheet-rich conformations, which facilitates the fibrillization of the TDP-43311-360 peptide. Our MD and REST2 simulation results suggest that the 321-330 region is of paramount importance to α-to-β transition and could be the initiation site for TDP-43311-360 fibrillization. Our work reveals the mechanism underlying the enhanced aggregation propensity of the G335D TDP-43311-360 peptide, which provides atomistic insights into the G335D mutation-caused pathogenicity of TDP-43 protein.

Single Amino Acid Modifications for Controlling the Helicity of Peptide-Based Chiral Gold Nanoparticle Superstructures.

Assembling nanoparticles (NPs) into well-defined superstructures can lead to emergent collective properties that depend on their 3-D structural arrangement. Peptide conjugate molecules designed to both bind to NP surfaces and direct NP assembly have proven useful for constructing NP superstructures, and atomic- and molecular-level alterations to these conjugates have been shown to manifest in observable changes to nanoscale structure and properties. The divalent peptide conjugate, C16-(PEPAu)2 (PEPAu = AYSSGAPPMPPF), directs the formation of one-dimensional helical Au NP superstructures. This study examines how variation of the ninth amino acid residue (M), which is known to be a key Au anchoring residue, affects the structure of the helical assemblies. A series of conjugates of differential Au binding affinities based on variation of the ninth residue were designed, and Replica Exchange with Solute Tempering (REST) Molecular Dynamics simulations of the peptides on an Au(111) surface were performed to determine the approximate surface contact and to assign a binding score for each new peptide. A helical structure transition from double helices to single helices is observed as the peptide binding affinity to the Au(111) surface decreases. Accompanying this distinct structural transition is the emergence of a plasmonic chiroptical signal. REST-MD simulations were also used to predict new peptide conjugate molecules that would preferentially direct the formation of single-helical AuNP superstructures. Significantly, these findings demonstrate how small modifications to peptide precursors can be leveraged to precisely direct inorganic NP structure and assembly at the nano- and microscale, further expanding and enriching the peptide-based molecular toolkit for controlling NP superstructure assembly and properties.

Re-Balancing Replica Exchange with Solute Tempering for Sampling Dynamic Protein Conformations.

Replica exchange with solute tempering (REST) is a highly effective variant of replica exchange for enhanced sampling in explicit solvent simulations of biomolecules. By scaling the Hamiltonian for a selected "solute" region of the system, REST effectively applies tempering only to the degrees of freedom of interest but not the rest of the system ("solvent"), allowing fewer replicas for covering the same temperature range. A key consideration of REST is how the solute-solvent interactions are scaled together with the solute-solute interactions. Here, we critically evaluate the performance of the latest REST2 protocol for sampling large-scale conformation fluctuations of intrinsically disordered proteins (IDPs). The results show that REST2 promotes artificial protein conformational collapse at high effective temperatures, which seems to be a designed feature originally to promote the sampling of reversible folding of small proteins. The collapse is particularly severe with larger IDPs, leading to replica segregation in the effective temperature space and hindering effective sampling of large-scale conformational changes. We propose that the scaling of the solute-solvent interactions can be treated as free parameters in REST, which can be tuned to control the solute conformational properties (e.g., chain expansion) at different effective temperatures and achieve more effective sampling. To this end, we derive a new REST3 protocol, where the strengths of the solute-solvent van der Waals interactions are recalibrated to reproduce the levels of protein chain expansion at high effective temperatures. The efficiency of REST3 is examined using two IDPs with nontrivial local and long-range structural features, including the p53 N-terminal domain and the kinase inducible transactivation domain of transcription factor CREB. The results suggest that REST3 leads to a much more efficient temperature random walk and improved sampling efficiency, which also further reduces the number of replicas required. Nonetheless, our analysis also reveals significant challenges of relying on tempering alone for sampling large-scale conformational fluctuations of disordered proteins. It is likely that more efficient sampling protocols will require incorporating more sophisticated Hamiltonian replica exchange schemes in addition to tempering.

Elucidating TH301's influence on the torsion angle of CRY1 W399 using replica exchange with solute tempering (REST) molecular dynamics (MD) simulations.

Cryptochrome 1 (CRY1) is a protein involved in the circadian clock and associated with various diseases. Targeting CRY1 for drug development requires the discovery of competitive inhibitors that target its FAD binding site through ubiquitination. During the development of compounds to regulate CRY1, an intriguing compound called TH301 was identified. Despite binding to CRY1, TH301 does not induce the expected reaction and is considered an inactive compound. However, it has been observed that TH301 affects the torsion angle of CRY1's W399 residue, which plays a crucial role in the regulation of ubiquitination by influencing the movement of the lid loop. In our research, we aimed to understand how TH301 induces the torsion angle of CRY1's W399 to shift to an "out-form" by performing REST-based MD simulations. The cyclopentane of TH301 tends to align parallel with W292, creating a repulsive force when W399 is in the "in-form", leading to a flip. In the "out-form", W399's side chain interacts with TH301's chlorobenzene through a π-π interaction, stabilizing this pose. This analysis helps identify compounds binding to CRY1 and filter out inactive ones. We found that assessing the interaction energy between TH301 and W399 is crucial to evaluate whether W399 flips or not. These findings contribute to the development of drugs targeting CRY1 and enhance our understanding of its regulatory mechanisms.

Modified Hamiltonian in FEP Calculations for Reducing the Computational Cost of Electrostatic Interactions.

The free-energy perturbation (FEP) method predicts relative and absolute free-energy changes of biomolecules in solvation and binding with other molecules. FEP is, therefore, one of the most essential tools in in silico drug design. In conventional FEP, to smoothly connect two thermodynamic states, the potential energy is modified as a linear combination of the end-state potential energies by introducing scaling factors. When the particle mesh Ewald is used for electrostatic calculations, conventional FEP requires two reciprocal-space calculations per time step, which largely decreases the computational performance. To overcome this problem, we propose a new FEP scheme by introducing a modified Hamiltonian instead of interpolation of the end-state potential energies. The scheme introduces nonuniform scaling into the electrostatic potential as used in Replica Exchange with Solute Tempering 2 (REST2) and does not require additional reciprocal-space calculations. We tested this modified Hamiltonian in FEP calculations in several biomolecular systems. In all cases, the calculated free-energy changes with the current scheme are in good agreement with those from conventional FEP. The modified Hamiltonian in FEP greatly improves the computational performance, which is particularly marked for large biomolecular systems whose reciprocal-space calculations are the major bottleneck of total computational time.

Replica permutation with solute tempering for molecular dynamics simulation and its application to the dimerization of amyloid-β fragments.

We propose the replica permutation with solute tempering (RPST) by combining the replica-permutation method (RPM) and the replica exchange with solute tempering (REST). Temperature permutations are performed among more than two replicas in RPM, whereas temperature exchanges are performed between two replicas in the replica-exchange method (REM). The temperature transition in RPM occurs more efficiently than in REM. In REST, only the temperatures of the solute region, the solute temperatures, are exchanged to reduce the number of replicas compared to REM. Therefore, RPST is expected to be an improved method taking advantage of these methods. For comparison, we applied RPST, REST, RPM, and REM to two amyloid-β(16-22) peptides in explicit water. We calculated the transition ratio and the number of tunneling events in the temperature space and the number of dimerization events of amyloid-β(16-22) peptides. The results indicate that, in RPST, the number of replicas necessary for frequent random walks in the temperature and conformational spaces is reduced compared to the other three methods. In addition, we focused on the dimerization process of amyloid-β(16-22) peptides. The RPST simulation with a relatively small number of replicas shows that the two amyloid-β(16-22) peptides form the intermolecular antiparallel β-bridges due to the hydrophilic side-chain contact between Lys and Glu and hydrophobic side-chain contact between Leu, Val, and Phe, which stabilizes the dimer of the peptides.

Recalibrating replica exchange solute tempering for sampling disordered protein conformations

Replica exchange with solute tempering (REST) is a variant of the popular replica exchange (REX) method that is particularly suitable for enhanced sampling of protein conformational equilibria in explicit solvent. In REST, only the selected “solute” portion of the original Hamiltonian is scaled and subjected to effective tempering, requiring much fewer numbers of replicas for covering the same temperature range compared to the traditional REX. The efficiency of simulating protein folding ab initio even be further improved by REST2 where the energy gaps between low-to-high temperature replicas are narrowed to allow for more frequent reverse transitions as the solute-solvent interactions are weakened.

PyAutoFEP: An Automated Free Energy Perturbation Workflow for GROMACS Integrating Enhanced Sampling Methods.

Free energy perturbation (FEP) calculations are now routinely used in drug discovery to estimate the relative FEB (RFEB) of small molecules to a biomolecular target of interest. Using enhanced sampling can improve the correlation between predictions and experimental data, especially in systems with conformational changes. Due to the large number of perturbations required in drug discovery campaigns, the manual setup of FEP calculations is no longer viable. Here, we introduce PyAutoFEP, a flexible and open-source tool to aid the setup of RFEB FEP. PyAutoFEP is written in Python3, and automates the generation of perturbation maps, dual topologies, system building and molecular dynamics (MD), and analysis. PyAutoFEP supports multiple force fields, incorporates replica exchange with solute tempering (REST) and replica exchange with solute scaling (REST2) enhanced sampling methods, and allows flexible λ values along perturbation windows. To validate PyAutoFEP, it was applied to a set of 14 Farnesoid X receptor ligands, a system included in the drug design data resource grand challenge 2. An 88% mean correct sign prediction was achieved, and 75% of the predictions had an error below 1.5 kcal/mol. Results using Amber03/GAFF, CHARMM36m/CGenFF, and OPLS-AA/M/LigParGen had Pearson's r values of 0.71 ± 0.13, 0.30 ± 0.27, and 0.66 ± 0.20, respectively. The Amber03/GAFF and OPLS-AA/M/LigParGen results were on par with the top grand challenge 2 submissions. Applying REST2 improved the results using CHARMM36m/CGenFF (Pearson's r = 0.43 ± 0.21) but had little impact on the other force fields. CHARMM36-YF and CHARMM36-WYF modifications did not yield improved predictions compared to CHARMM36m. Finally, we estimated the probability of finding a molecule 1 pKi better than a lead when using PyAutoFEP to screen 10 or 100 analogues. The probabilities, when compared to random sampling, increased up to sevenfold when 100 molecules were to be screened, suggesting that PyAutoFEP would likely be useful for lead optimization. PyAutoFEP is available on GitHub at https://github.com/lmmpf/PyAutoFEP.

Structural Studies of Designed Chimeric Proteins and Predictions of Mutational Effects

Improved understanding of evolution would help address problems such as antibiotic resistance, cancer progression, and pathogen emergence. One challenge is the prediction of how mutations affect protein function and organismal fitness. We study Escherichia coli (E. coli) dihydrofolate reductase (DHFR) as a model system to understand how altering protein sequences affects phenotype and what evolutionary changes take place in response. We designed chimeric DHFR proteins in which a catalytically-important alpha-helical segment has been replaced with structurally-helical sequences from other proteins. Experimental characterizations of the chimeric proteins showed that stability was compromised and catalysis significantly impaired. In concert with this experimental work, we carried out computational simulations to understand how catalysis is impaired and what mutations may restore catalytic activity. Our computational approach uses replica exchange with solute tempering (REST) molecular dynamics (MD) simulations to characterize the conformational states of our chimeric proteins. We find that order parameters for the foldedness of the replacement helix correlate well with the catalytic properties of the DHFR chimeras. We additionally performed all-atom Monte Carlo simulations using a statistical potential. We observe that chimeric DHFRs more easily adopt partly unfolded conformations as a result of the lowered stability of the replacement helix region. We next aim to predict what mutations would restore DFHR activity, and we are planning experimental evolution of E. coli strains in which chimeric DHFRs have been individually incorporated into the bacterial chromosome.

Structural Characteristics of Monomeric Aβ42 on Fibril in the Early Stage of Secondary Nucleation Process.

Amyloid-β (Aβ) aggregates are believed to be one of the main causes of Alzheimer's disease. Aβ peptides form fibrils having cross β-sheet structures mainly through primary nucleation, secondary nucleation, and elongation. In particular, self-catalyzed secondary nucleation is of great interest. Here, we investigate the adsorption of Aβ42 peptides to the Aβ42 fibril to reveal a role of adsorption as a part of secondary nucleation. We performed extensive molecular dynamics simulations based on replica exchange with solute tempering 2 (REST2) to two systems: a monomeric Aβ42 in solution and a complex of an Aβ42 peptide and Aβ42 fibril. Results of our simulations show that the Aβ42 monomer is extended on the fibril. Furthermore, we find that the hairpin structure of the Aβ42 monomer decreases but the helix structure increases by adsorption to the fibril surface. These structural changes are preferable for forming fibril-like aggregates, suggesting that the fibril surface serves as a catalyst in the secondary nucleation process. In addition, the stabilization of the helix structure of the Aβ42 monomer on the fibril indicates that the strategy of a secondary nucleation inhibitor design for Aβ40 can also be used for Aβ42.

Capturing the Flexibility of a Protein-Ligand Complex: Binding Free Energies from Different Enhanced Sampling Techniques.

Enhanced sampling techniques are a promising approach to obtain reliable binding free-energy profiles for flexible protein-ligand complexes from molecular dynamics (MD) simulations. To put four popular enhanced sampling techniques to a biologically relevant and challenging test, we studied the partial dissociation of an antigenic peptide from the Major Histocompatibility Complex I (MHC I) HLA-B*35:01 to systematically investigate the performance of umbrella sampling (US), replica exchange with solute tempering 2 (REST2), bias exchange umbrella sampling (BEUS, or replica-exchange umbrella sampling), and well-tempered metadynamics (MTD). With regard to the speed of sampling and convergence, the peptide-MHC I complex (pMHC I) under study showcases intrinsic strengths and weaknesses of the four enhanced sampling techniques used. We found that BEUS can best handle the sampling challenges that arise from the coexistence of an enthalpically and an entropically stabilized free-energy minimum in the pMHC I under study. These findings might also be relevant for other flexible biomolecular systems with competing enthalpically and entropically stabilized minima.

Conformational states of Zika virus non-structural protein 3 determined by molecular dynamics simulations with small-angle X-Ray scattering data

Zika virus (ZIKV) has become a great public health emergency. Its non-structural protein 3 (NS3) is a key enzyme in viral replication and has been considered as a potential therapeutic target. A conformational characterization of ZIKV NS3 is critical for a comprehensive understanding of its molecular interactions and functions. However, the high conformational flexibility of solution NS3 obstacles the structural characterization of NS3 solely from the experimental observable that averages over its heterogeneous conformations. Here, we employed replica exchange with solute tempering (REST) method to simulate the di-domain protein ZIKV NS3. Three independent MD simulations identified a conserved conformational ensemble of NS3, consisting of a major conformational state and several minor states from compact to loose conformations. The major state agrees well with the scattering profile from small-angle X-ray scattering (SAXS) experiments. Moreover, the simulated ensemble is supported by a direct data-fitting result that requires both short- and long-range structural contacts to recover the experimental data. We discussed the interplay between simulation and experiment in ensemble construction of flexible biomolecules and shed light on the physically derived conformational ensembles.

Temperature-induced collapse of a disordered peptide observed by three sampling methods in molecular dynamics simulations.

The conformational ensembles of a disordered peptide, polyglutamine Q15, over a wide temperature range were sampled using multiple replicates of conventional molecular dynamics (cMD) simulations as well as two enhanced sampling methods, temperature replica exchange (TREMD) and replica exchange with solute tempering (REST). The radius of gyration, asphericity, secondary structure, and hydrogen bonding patterns were used for the comparison of the sampling methods. Overall, the three sampling methods generated similar conformational ensembles, with progressive collapse at higher temperatures. Although accumulating the longest simulation time (90 μs), cMD at room temperature missed a small subspace that was sampled by both TREMD and REST. This subspace was high in α-helical content and separated from the main conformational space by an energy barrier. REST used less simulation time than TREMD (36 μs versus 42 μs), and this gap is expected to widen significantly for larger disordered proteins. We conclude that REST is the method of choice for conformational sampling of intrinsically disordered proteins.

Efficient sampling of puckering states of monosaccharides through replica exchange with solute tempering and bond softening.

A molecular-level understanding of the structure, dynamics, and reactivity of carbohydrates is fundamental to the understanding of a range of key biological processes. The six-membered pyranose ring, a central component of biological monosaccharides and carbohydrates, has many different puckering conformations, and the conformational free energy landscape of these biologically important monosaccharides remains elusive. The puckering conformations of monosaccharides are separated by high energy barriers, which pose a great challenge for the complete sampling of these important conformations and accurate modeling of these systems. While metadynamics or umbrella sampling methods have been used to study the conformational space of monosaccharides, these methods might be difficult to generalize to other complex ring systems with more degrees of freedom. In this paper, we introduce a new enhanced sampling method for the rapid sampling over high energy barriers that combines our previously developed enhanced sampling method REST (replica exchange with solute tempering) with a bond softening (BOS) scheme that makes a chemical bond in the ring weaker as one ascends the replica ladder. We call this new method replica exchange with solute tempering and bond softening (REST/BOS). We demonstrate the superior sampling efficiency of REST/BOS over other commonly used enhanced sampling methods, including temperature replica exchange method and REST. The conformational free energy landscape of four biologically important monosaccharides, namely, α-glucose, β-glucose, β-mannose, and β-xylose, is studied using REST/BOS, and results are compared with previous experimental and theoretical studies.

Flexible selection of the solute region in replica exchange with solute tempering: Application to protein-folding simulations.

Replica-exchange molecular dynamics (REMD) and their variants have been widely used in simulations of the biomolecular structure and dynamics. Replica exchange with solute tempering (REST) is one of the methods where temperature of a pre-defined solute molecule is exchanged between replicas, while solvent temperatures in all the replicas are kept constant. REST greatly reduces the number of replicas compared to the temperature REMD, while replicas at low temperatures are often trapped under their conditions, interfering with the conformational sampling. Here, we introduce a new scheme of REST, referred to as generalized REST (gREST), where the solute region is defined as a part of a molecule or a part of the potential energy terms, such as the dihedral-angle energy term or Lennard-Jones energy term. We applied this new method to folding simulations of a β-hairpin (16 residues) and a Trp-cage (20 residues) in explicit water. The protein dihedral-angle energy term is chosen as the solute region in the simulations. gREST reduces the number of replicas necessary for good random walks in the solute-temperature space and covers a wider conformational space compared to the conventional REST2. Considering the general applicability, gREST should become a promising tool for the simulations of protein folding, conformational dynamics, and an in silico drug design.

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.

Communication: Self-assembly of a model supramolecular polymer studied by replica exchange with solute tempering

Conventional molecular-dynamics (cMD) simulation has a well-known limitation in accessible time and length scales, and thus various enhanced sampling techniques have been proposed to alleviate the problem. In this paper, we explore the utility of replica exchange with solute tempering (REST) (i.e., a variant of Hamiltonian replica exchange methods) to simulate the self-assembly of a supramolecular polymer in explicit solvent and compare the performance with temperature-based replica exchange MD (T-REMD) as well as cMD. As a test system, we consider a relatively simple all-atom model of supramolecular polymerization (namely, benzene-1,3,5-tricarboxamides in methylcyclohexane solvent). Our results show that both REST and T-REMD are able to predict highly ordered polymer structures with helical H-bonding patterns, in contrast to cMD which completely fails to obtain such a structure for the present model. At the same time, we have also experienced some technical challenge (i.e., aggregation-dispersion transition and the resulting bottleneck for replica traversal), which is illustrated numerically. Since the computational cost of REST scales more moderately than T-REMD, we expect that REST will be useful for studying the self-assembly of larger systems in solution with enhanced rearrangement of monomers.

Enhanced Sampling of Intrinsic Structural Heterogeneity of the BH3-Only Protein Binding Interface of Bcl-xL

Antiapoptotic Bcl-xL plays central roles in regulating programed cell death. Partial unfolding of Bcl-xL has been observed at the interface upon specific binding to the pro-apoptotic BH3-only protein PUMA, which in turn disrupts the interaction of Bcl-xL with tumor suppressor p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures and atomistic molecular dynamics (MD) simulations have suggested that substantial intrinsic structure heterogeneity exists at the BH3-only protein binding interface of Bcl-xL to facilitate its conformational transitions upon binding. In this study, enhanced sampling is applied to further characterize the interfacial conformations of unbound Bcl-xL in explicit solvent. Extensive replica exchange with solute tempering (REST) simulations, with a total accumulated time of 16 μs, were able to cover much wider conformational spaces for the interfacial region of Bcl-xL. The resulting structural ensembles are much better converged, with local and long-range structural features that are highly consistent with existing NMR data. These simulations further demonstrate that the BH3-only protein binding interface of Bcl-xL is intrinsically disordered and samples many rapidly interconverting conformations. Intriguingly, all previously observed conformers are well represented in the unbound structure ensemble. Such intrinsic structural heterogeneity and flexibility may be critical for Bcl-xL to undergo partial unfolding induced by PUMA binding, and likely provide a robust basis that allows Bcl-xL to respond sensitively to binding of various ligands in cellular signaling and regulation.

Sampling conformational space of intrinsically disordered proteins in explicit solvent: Comparison between well-tempered ensemble approach and solute tempering method

Intrinsically disordered proteins (IDPs) are a class of proteins that expected to be largely unstructured under physiological conditions. Due to their heterogeneous nature, experimental characterization of IDP is challenging. Temperature replica exchange molecular dynamics (T-REMD) is a widely used enhanced sampling method to probe structural characteristics of these proteins. However, its application has been hindered due to its tremendous computational cost, especially when simulating large systems in explicit solvent. Two methods, parallel tempering well-tempered ensemble (PT-WTE) and replica exchange with solute tempering (REST), have been proposed to alleviate the computational expense of T-REMD. In this work, we select three different IDP systems to compare the sampling characteristics and efficiencies of the two methods Both the two methods could efficiently sample the conformational space of IDP and yield highly consistent results for all the three IDPs. The efficiencies of the two methods: are compatible, with about 5–6 times better than the plain T-REMD. Besides, the advantages and disadvantages of each method are also discussed. Specially, the PT-WTE method could provide temperature dependent data of the system which could not be achieved by REST, while the REST method could readily be used to a part of the system, which is quite efficient to simulate some biological processes.

Does Replica Exchange with Solute Tempering Efficiently Sample Aβ Peptide Conformational Ensembles?

We have applied replica exchange with solute tempering (REST) molecular dynamics to study a short fragment of the Aβ peptide, Aβ25-35, in water and a much larger system incorporating two Aβ10-40 peptides binding to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer. As a control, we used traditional replica exchange molecular dynamics (REMD) applied to the same systems. Our objective was to assess the practical utility of REST simulations. Taken together, our results suggest four conclusions. First, compared to REMD, the number of replicas in REST simulations can be reduced four to five times without affecting the temperature range or compromising an efficient random walk of REST replicas over temperatures. Second, although overall REST produces much fewer conformational states than REMD, there is no substantial difference in the collection of unique states for the wild-type replica in REST and REMD, especially for the system featuring Aβ peptides binding to the lipid bilayer. Third, we performed a thorough comparison of REST and REMD equilibrium conformational ensembles, including thermal averages and probability distributions. REST reproduces REMD data extremely well for the system of Aβ peptides binding to the DMPC lipid bilayer. The agreement between REST and REMD equilibrium sampling of Aβ25-35 in water is less perfect, but it improves with addition of new REST simulations. Surprisingly, REST demonstrates much better convergence for the system featuring ordered peptides binding to lipid bilayer rather than for a small unstructured peptide solvated in water. Fourth, REST delivers its full computational advantage over REMD when applied to peptides interacting with lipid bilayers. For peptides solvated in water, REST does not appear to offer computational gain but may make replica simulations practically feasible due to a lower requirement for parallel computing environments. Our study is expected to facilitate wider application of REST in biomolecular simulations.