# Multi-Layer Free Energy Perturbation

## TL;DR

This paper introduces a multi-layer free energy perturbation method that improves sampling efficiency by allowing environmental relaxation during molecular dynamics, enabling faster and more accurate free energy calculations for drug design.

## Contribution

The paper proposes a novel multi-ensemble ansatz, MLFEP, addressing sampling inefficiency in FEP by incorporating environmental relaxation during MD simulations.

## Key findings

- MLFEP allows environmental reorganization during sampling.
- It reduces the need for enhanced sampling methods.
- Enables faster, accurate free energy calculations.

## Abstract

Free energy perturbation (FEP) is frequently used to evaluate the free energy change of a biological process, e.g. the drug binding free energy or the ligand solvation free energy. Due to the sampling inefficiency, FEP is often employed together with computationally expensive enhanced sampling methods. Here we show that this sampling inefficiency, which stems from not accounting for the environmental reorganization, is an inherent property of the single-ensemble ansatz of FEP, and hence simply prolonging the MD simulation can hardly alleviate the problem. Instead, we propose a new, multi-ensemble ansatz -- the multi-layer free energy perturbation (MLFEP), which allows environmental reorganization processes (relaxation) to occur automatically during the MD sampling. Our study paves the way toward a fast but accurate free energy calculation that can be employed in computer-aided drug design.