Combining the biased and unbiased sampling strategy into one convenient free energy calculation method

Abstract

Constructing a free energy landscape for a large molecule is difficult. One has to use either a high temperature or a strong driving force to enhance the sampling on the free energy barriers. In this work, we propose a mixed method that combines these two kinds of acceleration strategies into one simulation. First, it applies an adaptive biasing potential to some replicas of the molecule. These replicas are particularly accelerated in a collective variable space. Second, it places some unbiased and exchangeable replicas at various temperature levels. These replicas generate unbiased sampling data in the canonical ensemble. To improve the sampling efficiency, biased replicas transfer their state variables to the unbiased replicas after equilibrium by Monte Carlo trial moves. In comparison to previous integrated methods, it is more convenient for users. It does not need an initial reference biasing potential to guide the sampling of the molecule. And it is also unnecessary to insert many replicas for the requirement of passing the free energy barriers. The free energy calculation is accomplished in a single stage. It samples the data as fast as a biased simulation and it processes the data as simple as an unbiased simulation. The method provides a minimalist approach to the construction of the free energy landscape. © 2019 Wiley Periodicals, Inc.

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

“…Currently there are five sampling methods implemented in FSATOOL: mixing REMD, SMD, essential dynamics sampling (EDS), ABMD, and standard REMD . For example, mixing REMD requires a set of collective variables to be included in the biasing potential. When the simulation is done, it provides the unbiased trajectories of Cartesian coordinates or collective variables.…”

“…In the simulation performed by pmemd.cuda of AMBER, the sampling module of FSATOOL is called at every MD step. According to the name list “task” in the input file, different sampling methods can be applied to the simulation, including the mixing REMD method that has all the advantages with the biased and unbiased sampling strategies . The method is introduced and tested well in our previous paper .…”

“…According to the name list “task” in the input file, different sampling methods can be applied to the simulation, including the mixing REMD method that has all the advantages with the biased and unbiased sampling strategies . The method is introduced and tested well in our previous paper . In this work, we write an interface of the method to the sampling module of FSATOOL.…”

“…Recently, we propose a mixing REMD method . It combines the biased simulation with the unbiased simulation.…”

“…First, FSATOOL implements the mixing REMD sampling method. As discussed in our previous paper, the method accelerates the simulation by the artificial potential and the high temperature simultaneously. The former is for the fast sampling in the collective variable space and the latter is for the global searching in the conformational space.…”