Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces

Hanka Venselaar,Gert Vriend,Remko Kp Kuipers,Maarten L Hekkelman,Tim Ah Te Beek

doi:10.1186/1471-2105-11-548

Abstract

BackgroundMany newly detected point mutations are located in protein-coding regions of the human genome. Knowledge of their effects on the protein's 3D structure provides insight into the protein's mechanism, can aid the design of further experiments, and eventually can lead to the development of new medicines and diagnostic tools.ResultsIn this article we describe HOPE, a fully automatic program that analyzes the structural and functional effects of point mutations. HOPE collects information from a wide range of information sources including calculations on the 3D coordinates of the protein by using WHAT IF Web services, sequence annotations from the UniProt database, and predictions by DAS services. Homology models are built with YASARA. Data is stored in a database and used in a decision scheme to identify the effects of a mutation on the protein's 3D structure and function. HOPE builds a report with text, figures, and animations that is easy to use and understandable for (bio)medical researchers.ConclusionsWe tested HOPE by comparing its output to the results of manually performed projects. In all straightforward cases HOPE performed similar to a trained bioinformatician. The use of 3D structures helps optimize the results in terms of reliability and details. HOPE's results are easy to understand and are presented in a way that is attractive for researchers without an extensive bioinformatics background.

Highlights

Many newly detected point mutations are located in protein-coding regions of the human genome
Input The intended users of HOPE are life scientists who neither routinely use protein structures nor bioinformatics in their research. Both HOPE’s input and its results are designed to be intuitive and simple, and all software used will run with default settings so that the user neither needs to set parameters nor needs to read documentation
Upon running 24 test cases, listed on the website, we realised that the present version of HOPE is useful and reliable in analysing point mutations

Summary

Introduction

Many newly detected point mutations are located in protein-coding regions of the human genome Knowledge of their effects on the protein’s 3D structure provides insight into the protein’s mechanism, can aid the design of further experiments, and eventually can lead to the development of new medicines and diagnostic tools. A considerable fraction of these mutations is located in proteincoding regions of the genome and can affect the structure and function of that protein, thereby causing a phenotypic effect Knowledge of these structural and functional effects can aid the design of further experiments and can eventually lead to the development of better disease diagnostics or even medicines to help cure patients. The analysis of mutations that cause the EEC syndrome, for example, revealed that some patients carry a mutation that disturbs dimerisation of the affected P63 protein [1] This information has triggered a search for drugs http://www.epistem.eu; [2]). The study of a mutation in the human

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