Computational Drug Discovery and Design

Chapter 22

Computational Analysis of Solvent Inclusion in Docking

Studies of Protein–Glycosaminoglycan Systems

Sergey A. Samsonov

Abstract

Glycosaminoglycans (GAGs) are a class of anionic linear periodic polysaccharides, which play a key role in
many cell signaling related processes via interactions with their protein targets. In silico analysis and, in
particular, application of molecular docking approaches to these systems still experience many challenges
including the need of proper treatment of solvent, which is crucial for protein–GAG interactions. Here, we
describe two methods which we developed, to include solvent in the docking studies of protein–GAG
systems: the first one allows to de novo predict favorable positions of water molecules as a part of a rigid
receptor to be used for further molecular docking; the second one utilizes targeted molecular dynamics in
explicit solvent for molecular docking.

Key wordsAtomic probes, Electrostatics-driven interactions, Explicit solvent, Free energy calcula-

tions, Glycosaminoglycans, Molecular docking, Solvent displacement, Targeted molecular dynamics

1 Introduction

Glycosaminoglycans (GAGs) represent a particular class of anionic

linear periodic polysaccharides made up repetitive disaccharide

units [1], interactions with their protein targets in the extracellular

matrix of the cell can crucially affect many important biological

processes such as cellular signaling, adhesion, and intercellular

communication [2]. These molecules are challenging for computa-

tional analysis using standard tools because of their various sulfa-

tion patterns [3], high flexibility, extensive conformational space

they access [4], and, as a consequence of their highly charged

nature, importance and abundance of electrostatics-driven [5, 6]

and, in particular, solvent-mediated interactions in the complexes

with their protein targets [7]. The amount of water molecules

observed in available experimental structures from the PDB for

protein–GAG interfaces is about one order higher than in protein–-

protein interfaces [8]. Although taking into account explicit water

molecules into molecular docking approaches was shown to

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_22,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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