Using the Fast Fourier Transform in Binding Free Energy Calculations

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.