Standard Replica Exchange Molecular Dynamics Research Articles

What Can Human-Guided Simulations Bring to RNA Folding?

Inspired by the recent success of scientific-discovery games for predicting protein tertiary and RNA secondary structures, we have developed an open software for coarse-grained RNA folding simulations, guided by human intuition. To determine the extent to which interactive simulations can accurately predict 3D RNA structures of increasing complexity and lengths (four RNAs with 22–47 nucleotides), an interactive experiment was conducted with 141 participants who had very little knowledge of nucleic acids systems and computer simulations, and had received only a brief description of the important forces stabilizing RNA structures. Their structures and full trajectories have been analyzed statistically and compared to standard replica exchange molecular dynamics simulations. Our analyses show that participants gain easily chemical intelligence to fold simple and nontrivial topologies, with little computer time, and this result opens the door for the use of human-guided simulations to RNA folding. Our experiment shows that interactive simulations have better chances of success when the user widely explores the conformational space. Interestingly, providing on-the-fly feedback of the root mean square deviation with respect to the experimental structure did not improve the quality of the proposed models.

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.

Greedy replica exchange algorithm for heterogeneous computing grids.

Replica exchange molecular dynamics (REMD) has become a valuable tool in studying complex biomolecular systems. However, its application on distributed computing grids is limited by the heterogeneity of this environment. In this study, we propose a REMD implementation referred to as greedy REMD (gREMD) suitable for computations on heterogeneous grids. To decentralize replica management, gREMD utilizes a precomputed schedule of exchange attempts between temperatures. Our comparison of gREMD against standard REMD suggests four main conclusions. First, gREMD accelerates grid REMD simulations by as much as 40 %. Second, gREMD increases CPU utilization rates in grid REMD by up to 60 %. Third, we argue that gREMD is expected to maintain approximately constant CPU utilization rates and simulation wall-clock times with the increase in the number of replicas. Finally, we show that gREMD correctly implements the REMD algorithm and reproduces the conformational ensemble of a short peptide sampled in our previous standard REMD simulations. We believe that gREMD can find its place in large-scale REMD simulations on heterogeneous computing grids.

Improving the replica-exchange molecular-dynamics method for efficient sampling in the temperature space.

Replica-exchange molecular dynamics (REMD) is a popular sampling method in the molecular simulation. By frequently exchanging the replicas at different temperatures, the molecule can jump out of the minima and sample efficiently in the conformational space. Although REMD has been shown to be practical in a lot of applications, it does have a critical limitation. All the replicas at all the temperatures must be simulated for a period between the replica-exchange steps. This may be problematic for the reaction with high free energy barriers. In that case, too many replicas are required in the simulation. To reduce the calculation quantity and improve its performance, in this paper we propose a modified REMD method. During the simulation, each replica at each temperature can stay in either the active or inactive state and only switch between the states at the exchange step. In the active state, the replica moves freely in the canonical ensemble by the normal molecular dynamics, and in the inactive state, the replica is frozen temporarily until the next exchange step. The number of the replicas in the active states (active replicas) depends on the number of CPUs in the computer. Using the additional inactive replicas, one can perform an REMD simulation in a wider temperature space. The practical applications show that the modified REMD method is reliable. With the same number of active replicas, this REMD method can produce a more reasonable free energy surface around the free energy minima than the standard REMD method.

Reordering Hydrogen Bonds Using Hamiltonian Replica Exchange Enhances Sampling of Conformational Changes in Biomolecular Systems

Hydrogen bonds play an important role in stabilizing (meta-)stable states in protein folding. Hence, they can potentially be used as a way to bias these states in molecular simulation methods. Previously, Wolf et al. showed that applying repulsive and attractive hydrogen bond biasing potentials in an alternating way significantly accelerates the folding process (Wolf, M. G.; de Leeuw, S. W. Biophys. J. 2008, 94, 3742). As the biasing potentials are only active during a fixed time interval, this alternating scheme does not represent a thermodynamic equilibrium. In this work, we present a Hamiltonian replica exchange molecular dynamics (REMD) scheme that aims to shuffle and reorder hydrogen bonds in the protein backbone. We therefore apply adapted hydrogen bond potentials in a Hamiltonian REMD scheme, which we call hydrogen bond switching (HS). To compare the performance of the HS to a standard REMD method, we performed HS and temperature REMD simulations of a beta-heptapeptide in methanol. Both methods sample the conformational space to a similar extent. As the HS simulation required only five replicas, while the REMD simulation required 20 replicas, the HS method is significantly more efficient. We tested the HS method also on a larger system, 16-residue polyalanine in water. Both of the simulations starting from a completely unfolded and a folded conformation resulted in an ensemble with, apart from the starting structure, similar conformational minima. We can conclude that the HS method provides an efficient way to sample the conformational space of a protein, without requiring knowledge of the folded states beforehand. In addition, these simulations revealed that convergence was hampered by replicas having a preference for specific biasing potentials. As this sorting effect is inherent to any Hamiltonian REMD method, finding a solution will result in an additional increase in the efficiency of Hamiltonian REMD methods in general.

Coupling of replica exchange simulations to a non-Boltzmann structure reservoir.

Computing converged ensemble properties remains challenging for large biomolecules. Replica exchange molecular dynamics (REMD) can significantly increase the efficiency of conformational sampling by using high temperatures to escape kinetic traps. Several groups, including ours, introduced the idea of coupling replica exchange to a pre-converged, Boltzmann-populated reservoir, usually at a temperature higher than that of the highest temperature replica. This procedure reduces computational cost because the long simulation times needed for extensive sampling are only carried out for a single temperature. However, a weakness of the approach is that the Boltzmann-weighted reservoir can still be difficult to generate. We now present the idea of employing a non-Boltzmann reservoir, whose structures can be generated through more efficient conformational sampling methods. We demonstrate that the approach is rigorous and derive a correct statistical mechanical exchange criterion between the reservoir and the replicas that drives Boltzmann-weighted probabilities for the replicas. We test this approach on the trpzip2 peptide and demonstrate that the resulting thermal stability profile is essentially indistinguishable from that obtained using very long (>100 ns) standard REMD simulations. The convergence of this reservoir-aided REMD is significantly faster than for regular REMD. Furthermore, we demonstrate that modification of the exchange criterion is essential; REMD simulations using a standard exchange function with the non-Boltzmann reservoir produced incorrect results.

Improving Convergence of Replica-Exchange Simulations through Coupling to a High-Temperature Structure Reservoir.

Parallel tempering or replica-exchange molecular dynamics (REMD) significantly increases the efficiency of conformational sampling for complex molecular systems. However, obtaining converged data with REMD remains challenging, especially for large systems with complex topologies. We propose a new variant to REMD where the replicas are also permitted to exchange with an ensemble of structures that have been generated in advance using high-temperature MD simulations, similar in spirit to J-walking methods. We tested this approach on two non-trivial model systems, a β-hairpin and a 3-stranded β-sheet and compared the results to those obtained from very long (>100 ns) standard REMD simulations. The resulting ensembles were indistinguishable, including relative populations of different conformations on the unfolded state. The use of the reservoir is shown to significantly reduce the time required for convergence.