A Parallel-pulling Protocol for Free-Energy Evaluation

TL;DR

This paper introduces a parallel-pulling protocol based on step-wise procedures and mutual overlap criteria to efficiently compute free energy differences in molecular simulations, reducing computational costs and improving reliability.

Contribution

It presents a novel proof of Jarzynski's equality using step-wise pulling and proposes parallel protocols with overlap criteria for accurate free energy estimation.

Findings

Requires only 21 parallel simulations for deca-alanine

Achieves about 13% uncertainty with 0.4 ns relaxation time

Provides an alternative formula for free energy calculation

Abstract

Jarzynski's equality (JE) allows us to compute free energy differences from distributions of work. In molecular dynamics simulations, the traditional way of constructing work distributions is to perform as many pulling simulations as possible. But reliable work distributions are not always produced in a finite number of simulations. The computational cost of using JE is not less than other commonly used methods such as Thermodynamic Integration and Umbrella Sampling methods. Here we first show a different proof of JE based on the idea of step-wise pulling procedures that is efficient in computing free energies by using JE. The key point in our proof is that the processes of turning-on/off a harmonic potential to perform work are described by double Heaviside functions of time. We then show that the distributions of work performed by the potential can be easily generated from the distributions of a reaction coordinate along a pathway. Based on the proof, we propose sequential and parallel step-wise pulling protocols for generating work distributions that require suitable relaxation time at each pulling step. The criterion for reliable work distributions is that there must be sufficient mutual overlaps between the adjacent distributions of the reaction coordinate along the pathway. We arrive at an alternative formula (besides JE) to compute free energy differences from the averaged values of the reaction coordinate. The combination of JE and the alternative formula provides a viable way to determine the accuracy of computed free energy differences. For the stretching of a deca-alanine molecule, our approach requires 21 parallel simulations and relaxation time as small as 0.4 ns for each simulation to estimate free energy differences with an uncertainty of about 13%.