Improved Efficiency of Replica Exchange Simulations through Use of a Hybrid Explicit/Implicit Solvation Model

Abstract

The use of parallel tempering or replica exchange molecular dynamics (REMD) simulations has facilitated the exploration of free energy landscapes for complex molecular systems, but application to large systems is hampered by the scaling of the number of required replicas with increasing system size. Use of continuum solvent models reduces system size and replica requirements, but these have been shown to provide poor results in many cases, including overstabilization of ion pairs and secondary structure bias. Hybrid explicit/continuum solvent models can overcome some of these problems through an explicit representation of water molecules in the first solvation shells, but these methods typically require restraints on the solvent molecules and show artifacts in water properties due to the solvation interface. We propose an REMD variant in which the simulations are performed with a fully explicit solvent, but the calculation of exchange probability is carried out using a hybrid model, with the solvation shells calculated on the fly during the fully solvated simulation. The resulting reduction in the perceived system size in the REMD exchange calculation provides a dramatic decrease in the computational cost of REMD, while maintaining a very good agreement with results obtained from the standard explicit solvent REMD. We applied several standard and hybrid REMD methods with different solvent models to alanine polymers of 1, 3, and 10 residues, obtaining ensembles that were essentially independent of the initial conformation, even with explicit solvation. Use of only a continuum model without a shell of explicit water provided poor results for Ala3 and Ala10, with a significant bias in favor of the α-helix. Likewise, using only the solvation shells and no continuum model resulted in ensembles that differed significantly from the standard explicit solvent data. Ensembles obtained from hybrid REMD are in very close agreement with explicit solvent data, predominantly populating polyproline II conformations. Inclusion of a second shell of explicit solvent was found to be unnecessary for these peptides.

Secondary Structure Bias in Generalized Born Solvent Models: Comparison of Conformational Ensembles and Free Energy of Solvent Polarization from Explicit and Implicit Solvation

“…The average secondary structure propensities and local conformational preferences of all residues in each simulation are given in Table 1. The overall agreement between independent simulations for each solvent model (as indicated by the small error values) shows that good convergence was achieved for all simulations; excellent convergence for these ensembles has been reported previously 21 .…”

“…The distribution of temperatures was chosen to ensure good overlap of potential energy between replicas and to achieve an exchange acceptance ratio of 0.20. The TIP3P REMD simulations involved 40 replicas at temperatures ranging from 266.9 to 571.2 K. Since the GB REMD simulations had far fewer degrees of freedom, only 8 replicas were required at temperatures ranging from 269.5 to 570.9 K. All data analysis was performed on REMD structure ensembles at 300.0 K. The high degree of convergence of these ensembles has been demonstrated in a previously published study 21 .…”

Comparison of multiple Amber force fields and development of improved protein backbone parameters

“…If, for example, PP II is indeed stabilized by specific interactions with explicit water as recently suggested 57,66-68 , such stabilization is not possible with implicit solvents, and thus structural preference may change. In fact, we recently reported that GB solvation models increase α-helical propensity 69 . Different approaches in force field development might be needed to account for these effects, and force fields should likely be tested with the particular characteristics (and perhaps idiosyncrasies) of these models in mind.…”

“…For example, the improved glycine parametrization was important in our recent simulations of HIV-1 protease 70 , where glycine rich "flaps" play an essential role in protease dynamics. Another study 69 reported a hybrid replica exchange method, where ff99SB was used to test the methodology based on conformational sampling of polyalanine peptides of varying lengths. Our recent simulations 71 of fragments of the villin headpiece with ff99SB also achieved good agreement with experimental trends 72 in calculated J-coupling constants and helical propensities.…”

Conformational flexibility of N-glycans in solution studied by REMD simulations

“…The application of the REMD method to larger protein-glycan systems requires a large number of replicas. There have been several attempts to reduce the number of replicas, such as using REMD with a hybrid explicit/implicit solvation model (Okur et al 2006), solute tempering (Liu et al 2005), and REMD coupled to a high-temperature structure reservoir (Okur et al 2007). Such methods and further methodological developments could lead to accurate free-energy calculations of protein-glycan binding, and help explore the relationship between the flexibility of glycans and their specific recognition.…”