Hybrid Cascade-Type Molecular Dynamics with a Markov State Model for Efficient Free Energy Calculations.

A protocol for calculating free energy landscapes (FELs) is proposed based on a combination of two cascade-type molecular dynamics (MD) methods, parallel cascade selection MD (PaCS-MD) and outlier flooding method (OFLOOD), with the help of a Markov state model (MSM). The former rapidly generates approximated transition paths directly connecting reactants with products, and the latter complementary resamples marginal conformational subspaces. Trajectories obtained by them give reliable microstates in MSM providing accurate FEL with low computational costs. As a demonstration, the present method was applied to a miniprotein (Chignolin and Trp-cage) in explicit water and successfully elucidated multiple folding paths on their free energy landscapes. Our method could be applicable to a wide variety of biological systems to estimate their free energy profiles.