TIGER2 with solvent energy averaging (TIGER2A): An accelerated sampling method for large molecular systems with explicit representation of solvent.

Abstract

The recently developed "temperature intervals with global exchange of replicas" (TIGER2) accelerated sampling method is found to have inaccuracies when applied to systems with explicit solvation. This inaccuracy is due to the energy fluctuations of the solvent, which cause the sampling method to be less sensitive to the energy fluctuations of the solute. In the present work, the problem of the TIGER2 method is addressed in detail and a modification to the sampling method is introduced to correct this problem. The modified method is called "TIGER2 with solvent energy averaging," or TIGER2A. This new method overcomes the sampling problem with the TIGER2 algorithm and is able to closely approximate Boltzmann-weighted sampling of molecular systems with explicit solvation. The difference in performance between the TIGER2 and TIGER2A methods is demonstrated by comparing them against analytical results for simple one-dimensional models, against replica exchange molecular dynamics (REMD) simulations for sampling the conformation of alanine dipeptide and the folding behavior of (AAQAA)3 peptide in aqueous solution, and by comparing their performance in sampling the behavior of hen egg-white lysozyme in aqueous solution. The new TIGER2A method solves the problem caused by solvent energy fluctuations in TIGER2 while maintaining the two important characteristics of TIGER2, i.e., (1) using multiple replicas sampled at different temperature levels to help systems efficiently escape from local potential energy minima and (2) enabling the number of replicas used for a simulation to be independent of the size of the molecular system, thus providing an accelerated sampling method that can be used to efficiently sample systems considered too large for the application of conventional temperature REMD.