Boosting the conformational sampling by combining replica exchange with solute tempering and well‐sliced metadynamics

Abstract

Methods that combine collective variable (CV) based enhanced sampling and global tempering approaches are used in speeding‐up the conformational sampling and free energy calculation of large and soft systems with a plethora of energy minima. In this paper, a new method of this kind is proposed in which the well‐sliced metadynamics approach (WSMTD) is united with replica exchange with solute tempering (REST2) method. WSMTD employs a divide‐and‐conquer strategy wherein high‐dimensional slices of a free energy surface are independently sampled and combined. The method enables one to accomplish a controlled exploration of the CV‐space with a restraining bias as in umbrella sampling, and enhance‐sampling of one or more orthogonal CVs using a metadynamics like bias. The new hybrid method proposed here enables boosting the sampling of more slow degrees of freedom in WSMTD simulations, without the need to specify associated CVs, through a replica exchange scheme within the framework of REST2. The high‐dimensional slices of the probability distributions of CVs computed from the united WSMTD and REST2 simulations are subsequently combined using the weighted histogram analysis method to obtain the free energy surface. We show that the new method proposed here is accurate, improves the conformational sampling, and achieves quick convergence in free energy estimates. We demonstrate this by computing the conformational free energy landscapes of solvated alanine tripeptide and Trp‐cage mini protein in explicit water.

Exploration of high dimensional free energy landscapes by a combination of temperature‐accelerated sliced sampling and parallel biasing

“…The free energy barriers Q ′ → P ′ and Q ′ → R ′ on the PBTASS‐computed surface are 6.2 and 7.1 kcal mol −1 , respectively, while the reverse barriers P ′ → Q ′ and R ′ → Q ′ , are 4.5 and 5.4 kcal mol −1 , respectively. It was also found in the earlier studies 28,76 that the free energy barriers on the F ( ϕ 1 , ϕ 2 ) surface for the case of solvated peptide are lower than the case of peptide in vacuo . In our earlier study using the globally accelerated sliced sampling (GASS) technique, 28 both Q ′ → P ′ and Q ′ → R ′ barriers were found to be 6.0 kcal mol −1 .…”

“…It was also found in the earlier studies 28,76 that the free energy barriers on the F ( ϕ 1 , ϕ 2 ) surface for the case of solvated peptide are lower than the case of peptide in vacuo . In our earlier study using the globally accelerated sliced sampling (GASS) technique, 28 both Q ′ → P ′ and Q ′ → R ′ barriers were found to be 6.0 kcal mol −1 . Similarly, P ′ → Q ′ and R ′ → Q ′ barrier estimates from GASS simulations are 4.4 kcal mol −1 .…”

“…Q 0 , are 4.5 and 5.4 kcal mol À1 , respectively. It was also found in the earlier studies 28,76 that the free energy barriers on the F(ϕ 1 ,ϕ 2 ) surface for the case of solvated peptide are lower than the case of peptide in vacuo. In our earlier study using the globally accelerated sliced sampling (GASS) technique, 28 both Q 0 !…”

“…Such transitions are classified as rare‐events in molecular simulations. Several enhanced sampling methods have been developed to accelerate such rare‐events in molecular dynamics (MD) simulations 1–35 . A subset of these techniques is based on enhanced sampling of collective variables (CVs), .…”

Enhanced sampling methods for molecular dynamics simulations

“…Furthermore, the metadynamics bias potential within each umbrella window helps to sample degrees of freedom that are orthogonal to the CV biased in the umbrella sampling simulations and thus improve the convergence. This combined umbrella sampling and metadynamics strategy has been extended to incorporate temperature accelerated MD [341,342] or replica exchange with solute tempering (REST2) [343] to further improve the sampling of orthogonal degrees of freedom.…”