Computational Drug Discovery and Design

Chapter 11

Absolute Alchemical Free Energy Calculations for Ligand

Binding: A Beginner’s Guide

Matteo Aldeghi, Joseph P. Bluck, and Philip C. Biggin

Abstract

Many thermodynamic quantities can be extracted from computer simulations that generate an ensemble of
microstates according to the principles of statistical mechanics. Among these quantities is the free energy of
binding of a small molecule to a macromolecule, such as a protein. Here, we present an introductory
overview of a protocol that allows for the estimation of ligand binding free energies via molecular dynamics
simulations. While we focus on the binding of organic molecules to proteins, the approach is in principle
transferable to any pair of molecules.

Key wordsFree energy, Computer simulations, Molecular dynamics, Alchemical transitions, Pro-

tein–ligand binding, Binding free energy, Binding affinity, Drug design, Molecular modeling

1 Introduction

The accurate prediction of the affinity of a drug for its target protein

has long been a central objective of structure-based drug design. As

such, many computational approaches that try to calculate or

approximate binding free energy have been developed [1, 2].

These range from fast scoring functions [3], to implicit-solvent

approaches based on the postprocessing of simulation snapshots

[4], to the more rigorous yet computationally expensive free energy

methods [2]. In particular, alchemical free energy calculations

based on all-atom molecular dynamic (MD) simulations in explicit

solvent are one of the approaches that operate at the highest level of

theoretical rigor, calculating free energy differences from well-

founded statistical mechanics principles and naturally including

entropic and solvent effects. These calculations are based on a

thermodynamic cycle that include a series of nonphysical interme-

diate states (hence the namealchemical), from which the free

energy difference between two physical end states can be recovered

Mohini Gore and Umesh B. Jagtap (eds.),Computational Drug Discovery and Design, Methods in Molecular Biology, vol. 1762,
https://doi.org/10.1007/978-1-4939-7756-7_11,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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