Computational Drug Discovery and Design

Chapter 19

Calculation of Thermodynamic Properties of Bound Water

Molecules

Ying Yang, Amr H. A. Abdallah, and Markus A. Lill

Abstract

Water molecules in the binding site of a protein significantly influence protein structure and function, for
example, by mediating protein–ligand interactions or in form of desolvation as driving force for ligand
binding. The knowledge about location and thermodynamic properties of water molecules in the binding
site is crucial to the understanding of protein function. This chapter describes the method of calculating the
location and thermodynamic properties of bound water molecules from molecular dynamics
(MD) simulation trajectories. Thermodynamic profiles of water molecules can be calculated either with
or without the presence of a bound ligand based on the scientific problem. The location and thermody-
namic profile of hydration sites mediating the protein–ligand interactions is important for understanding
protein–ligand binding. The protein desolvation free energy can be estimated for any ligand by summation
of the hydration site free energies of the displaced hydration sites. The WATsite program with an easy-to-use
graphical user interface (GUI) based on PyMOL was developed for those calculations and is discussed in
this chapter. The WATsite program and its PyMOL plugin are available free of charge fromhttp://people.
pharmacy.purdue.edu/~mlill/software/watsite/version3.shtml.

Key wordsDesolvation, Hydration site, Molecular dynamics, Protein desolvation free energy,

PyMOL, Solvation, Water thermodynamics, Water models, Water molecule, WATsite

1 Introduction

Water is a crucial participant in virtually all protein functions, e.g.,

protein folding [1–6] and ligand binding [7–10]. Binding site

water contributes significantly to the strength of intermolecular

interactions in the aqueous phase by mediating protein–ligand

interactions, solvating and desolvating both ligand and protein

upon ligand binding and unbinding [9, 11–14].

In structure-based drug design, a ligand is often modified to

displace ordered water molecules in the binding site. Due to the

inherent entropic contributions, releasing an ordered water mole-

cule from the binding site into the bulk solvent is thought to be

favorable for protein–ligand binding. However, in some cases the

enthalpic gain from extra water-mediated hydrogen bonds exceeds

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_19,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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