Implicit Ligand Theory: Rigorous Binding Free Energies and Thermodynamic Expectations from Molecular Docking

TL;DR

This paper introduces Implicit Ligand Theory, a formalism for calculating binding free energies from molecular docking that separates receptor and ligand sampling, enabling efficient virtual screening and providing insights into molecular recognition.

Contribution

It presents a rigorous formalism for estimating binding free energies that separates receptor and ligand sampling, improving virtual screening methods.

Findings

Good agreement with previous free energy calculations

Consistent with calorimetry measurements

Provides guidance for improving docking algorithms

Abstract

A rigorous formalism for estimating noncovalent binding free energies and thermodynamic expectations from calculations in which receptor configurations are sampled independently from the ligand is derived. Due to this separation, receptor configurations only need to be sampled once, facilitating the use of binding free energy calculations in virtual screening. Demonstrative calculations on a host-guest system yield good agreement with previous free energy calculations and isothermal titration calorimetry measurements. Implicit ligand theory provides guidance on how to improve existing molecular docking algorithms and insight into the concepts of induced fit and conformational selection in noncovalent macromolecular recognition.