Absolute FKBP binding affinities obtained via non-equilibrium unbinding simulations

TL;DR

This paper presents a straightforward non-equilibrium simulation method for accurately estimating absolute binding affinities of ligands to proteins, showing promising results close to experimental values.

Contribution

The study introduces a simple non-equilibrium unbinding approach that requires minimal modifications to existing molecular simulation tools, avoiding complex alchemical schemes.

Findings

Binding affinities estimated within 4.0 kJ/mol of target values

Target values within 1.0 kJ/mol of experimental data

Method shows promise for robust affinity estimation

Abstract

We compute absolute binding affinities for two ligands bound to the FKBP protein using non-equilibrium unbinding simulations. The methodology is straight-forward, requiring little or no modification to many modern molecular simulation packages. The approach makes use of a physical pathway, eliminating the need for complicated alchemical decoupling schemes. Results of this study are promising. For the ligands studied here the binding affinities are typically estimated within less than 4.0 kJ/mol of the target values; and the target values are within less than 1.0 kJ/mol of experiment. These results suggest that non-equilibrium simulation could provide a simple and robust means to estimate protein-ligand binding affinities.