Computational Drug Discovery and Design

Chapter 4

Phylogenetic and Other Conservation-Based Approaches

to Predict Protein Functional Sites

Heval Atas, Nurcan Tuncbag, and Tunca Dog ̆an

Abstract

Proteins use their functional regions to exploit various activities, including binding to other proteins,
nucleic acids, or drugs. Functional sites of the proteins have a tendency to be more conserved than the rest
of the protein surface. Therefore, detection of the conserved residues using phylogenetic analysis is a
general approach to predict functionally critical residues. In this chapter, we describe some of the available
methods to predict functional sites and demonstrate a complete pipeline with tool alternatives at several
steps. We explain the standard procedure and all intermediate stages including homology detection with
BLAST search, multiple sequence alignment (MSA) and the construction of a phylogenetic tree for a given
query sequence. Additionally, we demonstrate the prediction results of these methods on a case study.
Finally, we discuss the possible challenges and bottlenecks throughout the pipeline. Our step-by-step
description about the functional site prediction could be a helpful resource for the researchers interested
in finding protein functional sites, to be used in drug discovery research.

Key wordsDrug discovery, Evolutionary conservation, Functional site, Multiple sequence alignment,

Phylogenetic analysis, Predictive approaches

1 Introduction

Proteins do not act in isolation, rather they interact with other

molecules such as proteins, nucleic acids and small molecules

through their functional sites. Therefore, identification of the func-

tional sites is crucial to determine the function and activity of

proteins in a cell, which eventually helps in site-specific drug design

to inhibit pathological effect of the disease-related protein interac-

tions. The Universal Protein Resource (UniProt) is a knowledge-

base that provides comprehensive protein sequence and

annotations, including functions [1]. The majority of the published

information about the properties of proteins are organized and

recorded in UniProt protein pages. These annotations cover both

the experimentally known information and the results of some

major computational (i.e., predictive) approaches. Functional sites

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_4,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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