A Residence-Time Approach for Determining Position-Dependent Diffusivities from Biased Molecular Simulations

TL;DR

The paper presents a residence-time approach (RTA) for accurately determining position-dependent diffusivities from biased molecular dynamics simulations without requiring complex noise filtering or harmonic restraints.

Contribution

The RTA method provides a direct and practical way to extract local diffusivities from biased simulations, validated across multiple membrane systems.

Findings

RTA reproduces bulk diffusivities within statistical uncertainty.

Diffusivity profiles are validated by propagator-level analysis.

Method is applicable to various membrane permeation scenarios.

Abstract

We introduce a residence-time approach (RTA) for determining position-dependent diffusivities from biased molecular dynamics simulations. The method is formulated for trajectory segments in which the effective drift along the transport coordinate is negligible, as realized here using adaptive biasing force simulations. In this regime, local diffusivities are obtained directly from mean first-exit times out of finite spatial intervals. Unlike conventional fluctuation-based approaches, the RTA does not require dedicated harmonically restrained simulations or numerical integration of noisy time-correlation functions. We assess the method for oxygen diffusion across a hexadecane slab, water permeation across a lipid bilayer, and permeation of water and selected volatile organic compounds through a model skin-barrier membrane. In the slab system, the RTA reproduces independently determined bulk diffusivities within statistical uncertainty. In the membrane systems, the inferred diffusivity profiles are supported by propagator-level validation. These results establish the RTA as a practical approach for extracting position-dependent diffusivities from biased molecular simulations.