I. Dissociation free energies in drug-receptor systems via non equilibrium alchemical simulations: theoretical framework

TL;DR

This paper introduces a non-equilibrium alchemical simulation method for calculating drug-receptor binding free energies, addressing limitations of equilibrium approaches and enabling faster, more reliable estimates through multiple independent trajectories.

Contribution

It develops a non-equilibrium alchemical framework that improves binding free energy calculations by avoiding equilibrium assumptions and utilizing unidirectional estimates based on Crooks theorem.

Findings

Non-equilibrium simulations produce reliable free energy estimates.

Few hundred short trajectories suffice for accurate results.

The method exploits the funnel-like free energy surface in molecular recognition.

Abstract

In this contribution I critically revise the alchemical reversible approach in the context of the statistical mechanics theory of non covalent bonding in drug receptor systems. I show that most of the pitfalls and entanglements for the binding free energies evaluation in computer simulations are rooted in the equilibrium assumption that is implicit in the reversible method. These critical issues can be resolved by using a non-equilibrium variant of the alchemical method in molecular dynamics simulations, relying on the production of many independent trajectories with a continuous dynamical evolution of an externally driven alchemical coordinate, completing the decoupling of the ligand in a matter of few tens of picoseconds rather than nanoseconds. The absolute binding free energy can be recovered from the annihilation work distributions by applying an unbiased unidirectional free energy estimate, on the assumption that any observed work distribution is given by a mixture of normal distributions, whose components are identical in either direction of the non-equilibrium process, with weights regulated by the Crooks theorem. I finally show that the inherent reliability and accuracy of the unidirectional estimate of the decoupling free energies, based on the production of few hundreds of non-equilibrium independent sub-nanoseconds unrestrained alchemical annihilation processes, is a direct consequence of the funnel-like shape of the free energy surface in molecular recognition. An application of the technique on a real drug-receptor system is presented in the companion paper.