Using the Fast Fourier Transform in Binding Free Energy Calculations

TL;DR

This paper introduces a novel application of the Fast Fourier Transform (FFT) to efficiently compute binding free energies by estimating binding potentials of mean force, demonstrating good agreement with previous methods.

Contribution

The study is the first to apply FFT for rigorous binding free energy calculations, offering a new computational approach in the field.

Findings

FFT-based estimates agree well with previous calculations (R ~ 0.9 for 24 systems)

Effective for large datasets with 141 molecules, maintaining high accuracy (R ~ 0.8)

First use of FFT in this context for binding free energy estimation

Abstract

According to implicit ligand theory, the standard binding free energy is an exponential average of the binding potential of mean force (BPMF), an exponential average of the interaction energy between the ligand apo ensemble and a rigid receptor. Here, we use the Fast Fourier Transform (FFT) to efficiently estimate BPMFs by calculating interaction energies as rigid ligand configurations from the apo ensemble are discretely translated across rigid receptor conformations. Results for standard binding free energies between T4 lysozyme and 141 small organic molecules are in good agreement with previous alchemical calculations based on (1) a flexible complex (R ~ 0.9 for 24 systems) and (2) flexible ligand with multiple rigid receptor configurations (R ~ 0.8 for 141 systems). While the FFT is routinely used for molecular docking, to our knowledge this is the first time that the algorithm has been used for rigorous binding free energy calculations.