Computational Drug Discovery and Design

Chapter 17

Computational Exploration of Conformational Transitions

in Protein Drug Targets

Benjamin P. Cossins, Alastair D. G. Lawson, and Jiye Shi

Abstract

Protein drug targets vary from highly structured to completely disordered; either way dynamics governs
function. Hence, understanding the dynamical aspects of how protein targets function can enable improved
interventions with drug molecules. Computational approaches offer highly detailed structural models of
protein dynamics which are becoming more predictive as model quality and sampling power improve.
However, the most advanced and popular models still have errors owing to imperfect parameter sets and
often cannot access longer timescales of many crucial biological processes. Experimental approaches offer
more certainty but can struggle to detect and measure lightly populated conformations of target proteins
and subtle allostery. An emerging solution is to integrate available experimental data into advanced
molecular simulations. In the future, molecular simulation in combination with experimental data may be
able to offer detailed models of important drug targets such that improved functional mechanisms or
selectivity can be accessed.

Key wordsMolecular dynamics, Protein conformation, Conformational transition, Hidden pocket,

Allostery, Drug discovery

1 Nature of Conformational Space of Proteins

1.1 Structural
and Dynamical Nature
of Proteins

Protein is one of the fundamental materials of living organisms

along with RNA and DNA. The seemingly simple amino-acid

building blocks hide a stunning complexity of structure and dyna-

mical behavior. Proteins have evolved for particular functions and

their structural and dynamical nature reflects these functions.

Some proteins have very stable 3D structures such as crystal-

lins, which have evolved to form the transparent eye lens [1]. Other

proteins have no single stable structure but are dynamic ensembles

of various different conformations. These dynamic ensembles range

from the surprisingly prevalent intrinsically disordered proteins

(IDPs) to those with very specific and tightly ordered motions

like mechanical machine molecules. The mechanical-like protein

motions have been studied in an evolutionary context. These

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_17,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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