Computing committors via Mahalanobis diffusion maps with enhanced sampling data

TL;DR

This paper introduces an enhanced diffusion map method incorporating sampling techniques to accurately compute transition probabilities and pathways in molecular systems, addressing timescale challenges in molecular dynamics simulations.

Contribution

The paper develops the tm-mmap algorithm combining Mahalanobis diffusion maps with enhanced sampling to efficiently approximate the Backward Kolmogorov Operator for transition analysis.

Findings

Accurately computes committor functions and transition rates.

Successfully applied to complex molecular systems with multiple variables.

Outperforms finite element methods in high-dimensional cases.

Abstract

The study of phenomena such as protein folding and conformational changes in molecules is a central theme in chemical physics. Molecular dynamics (MD) simulation is the primary tool for the study of transition processes in biomolecules, but it is hampered by a huge timescale gap between the processes of interest and atomic vibrations which dictate the time step size. Therefore, it is imperative to combine MD simulations with other techniques in order to quantify the transition processes taking place on large timescales. In this work, the diffusion map with Mahalanobis kernel, a meshless approach for approximating the Backward Kolmogorov Operator (BKO) in collective variables, is upgraded to incorporate standard enhanced sampling techniques such as metadynamics. The resulting algorithm, which we call the "target measure Mahalanobis diffusion map" (tm-mmap), is suitable for a moderate number of collective variables in which one can approximate the diffusion tensor and free energy. Imposing appropriate boundary conditions allows use of the approximated BKO to solve for the committor function and utilization of transition path theory to find the reactive current delineating the transition channels and the transition rate. The proposed algorithm, tm-mmap, is tested on the two-dimensional Moro-Cardin two-well system with position-dependent diffusion coefficient and on alanine dipeptide in two collective variables where the committor, the reactive current, and the transition rate are compared to those computed by the finite element method (FEM). Finally, tm-mmap is applied to alanine dipeptide in four collective variables where the use of finite elements is infeasible.