Computational Drug Discovery and Design

Chapter 20

Enhanced Molecular Dynamics Methods Applied to Drug

Design Projects

Sonia Ziada, Abdennour Braka, Julien Diharce, Samia Aci-Se`che,

and Pascal Bonnet

Abstract

Nobel Laureate Richard P. Feynman stated: “[...] everything that living things do can be understood in
terms of jiggling and wiggling of atoms [...].” The importance of computer simulations of macromole-
cules, which use classical mechanics principles to describe atom behavior, is widely acknowledged and
nowadays, they are applied in many fields such as material sciences and drug discovery. With the increase of
computing power, molecular dynamics simulations can be applied to understand biological mechanisms at
realistic timescales. In this chapter, we share our computational experience providing a global view of two of
the widely used enhanced molecular dynamics methods to study protein structure and dynamics through
the description of their characteristics, limits and we provide some examples of their applications in drug
design. We also discuss the appropriate choice of software and hardware. In a detailed practical procedure,
we describe how to set up, run, and analyze two main molecular dynamics methods, the umbrella sampling
(US) and the accelerated molecular dynamics (aMD) methods.

Key wordsConformational sampling, Enhanced molecular dynamics, Free energy, Ligand (un)

binding

1 Introduction

Proteins are versatile organic macromolecules, which have specific

functions (transporter, reaction catalyzer, etc.) within living organ-

isms. Small molecules binding to the considered entity can control

this specific functionality. The formation of a drug–target complex

is the basis of action of most drugs. The lock-and-key model of the

early twentieth century, first formulated by Emil Fischer, gives a

static point of view of drug–target interactions. In this paradigm,

the binding is driven by shape complementarity between the ligand,

in one conformation, and the frozen binding site. Since this model

has been proposed, numerous evidences have revealed that proteins

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_20,©Springer Science+Business Media, LLC, part of Springer Nature 2018

Author contributed equally with all other contributors.Sonia Ziada and Abdennour Braka

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