Quick Guideline for Computational Drug Design

Sheikh Arslan Sehgal, A. Hammad Mirza, Rana Adnan Tahir

• Publisher: Bentham Science Publishers
• Year: 2018
• Print ISBN: 9781681086040
• eBook ISBN: 9781681086033
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

Bioinformatics allows researchers to answer biological questions with advanced computational methods which involves the application of statistics and mathematical modeling. Structural bioinformatics enables the prediction and analysis of 3D structures of

3D Structure Prediction

Sheikh Arslan Sehgal, A. Hammad Mirza, Rana Adnan Tahir

Abstract

The proteins having similar sequences may have similar structure” is the philosophy of sequences prediction techniques. The 3D structures have structural and functional importance for drug designing. Homology modeling, threading and ab initio approaches are the computational techniques to predict the 3D structure of the proteins for further studies. In this chapter, we will precisely elaborate numerous tools of 3D structure prediction.

Keywords: ab initio, Homology modeling, I-Tasser, MODELLER, Structure prediction, Threading.

Motivation

3D structure of a protein is important for the sequences and functional analysis of a protein. Experimentally determined structures through X-ray crystallography and Nuclear Magnetic Resonance (NMR) techniques provide detailed information related to the dynamics of the protein interactions with ligands, receptors, interacting proteins, and with its environment. There are 35,914 structures of human sequences available in PDB but still, usually the protein of interest may not have its structure solved through experimental techniques. In such conditions, it becomes necessary to have opted different methodologies for structural analyses. Computational methods are providing alternative ways to solve this problem by utilizing the structure prediction techniques. This chapter is aimed to introduce different desktop and web-based structure prediction methods. Many tools will be discussed and each tool implementing a different algorithm to model the protein structures. It will help the researchers and also the beginners to understand 3D structure prediction and can also compare the results according to the behavior of the protein of interest.

“The proteins having similar sequences may have similar structures” is the philosophy of structure prediction techniques. Due to unavailability of resources and time trade-offs, it is not possible to find the structure of proteins through X-ray crystallography and NMR techniques.

Structure prediction tools help to solve the 3D structure of proteins based on similarity (homology) of template protein structure with query protein (protein of interest). All of the structure prediction algorithms try to first align sequences of the protein of interest with the template(s), so first most important step in structure prediction is alignment. In this Chapter, we will follow the methodology of section 04 mentioned in Fig. (3).

Structure Prediction Tools

Protein structure prediction is an effort to predict the 3D structure of a protein from its amino acid sequence. The primary sequence also used to predict the folding and its secondary, tertiary, and quaternary structure (Mount et al., 2001).

A large number of protein structure predictions are very expensive and time consuming by X-Ray crystallography and NMR methods (Sehgal et al., 2014). Numerous computational approaches and tools for 3D structure prediction have been developed. It is critical that the biological community and beginners are aware of such tools and is able to interpret their results in an informed way. The elaborative methodology may provide a guideline to predict the 3D structure by different approaches and also interpret the results effectively.

Phyre2

Phyre2 is a structure prediction non-commercial tool and is able to regularly generate the reliable protein models (Lawrence et al., 2011).

Introduction

Phyre2 server predicts the 3D structure of target protein sequence by using homology modeling approach. It has been ranked amongst one of the best systems of its kind for the last four years as judged by the biannual Critical Assessment of Structure Prediction (CASP) meetings (Lawrence et al., 2011).

Brief Instructions

Following instructions should be followed in order to predict the 3D structure of the respective protein.

• Open the web browser
• Go to Phyre2 homepage (http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index)
• An interface will open where the amino acid sequence of the respective protein is uploaded e.g. RASSF2
• Provide the institutional e-mail ID ([email protected])
• Results will be sent through e-mail depending upon the sequence (query) length and number of protein sequences in queues

Requirements

Input

The input required for Phyre2 is the FASTA sequence of target protein retrieved from UniProt.

Sequence Submission

The FASTA sequence of RASSF2 submitted to phrex2 (Fig. 8).

Fig. (8))
RASSF2 Sequence submission to Phyre2.

Click on the “Phyre search” option and the generated 3D structure will send to the mentioned mail ID.

Results Interpretation (Results Screen)

The detailed information about the target protein (RASSF2) can be retrieved by opening the Phyre2 link sent to the user by e-mail containing results. The results screen of Phyre2 is divided into following main sections:

Secondary Structure and Disor...

Table of contents

• Welcome
• Table of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE
• Introduction to Structural Bioinformatics
• Protein Primary Sequence Analysis
• Secondary Structure Analyses
• 3D Structure Prediction
• Structure Evaluation
• Visualization of Predicted Structure
• Molecular Docking Studies