Protein Structure and Function. Application of Bioinformatics Methods - John Rigden 2014

Comparative Protein Structure Modeling
Introduction
Structure Determines Function

Andras Fiser

A prerequisite for understanding cellular function at a systems level is insight into the 3D Structure of Proteins, which mediate biochemical interactions. The rapid growth in the number of available protein sequences has laid the groundwork for the next phase of genome-scale projects: determining the Spatial Structure of every known protein. To achieve this ambitious goal, costly and time-consuming experimental structure determination is complemented by theoretical research approaches. This chapter provides An Overview of the Current state of the art in structural modeling and its recent advances, with a particular focus on comparative modeling techniques.

The functional characterization of proteins is one of the most pressing challenges in modern biology. Although protein sequences contain valuable functional information, functionally critical residues often cannot be identified due to high sequence plasticity (Todd et al. 2002). For instance, Enzymes with over 40% sequence identity may share the same function. However, when sequence identity drops to 30–40%, only the first three digits of the Enzyme Commission (EC) nomenclature can be reliably predicted, with an accuracy of just 90%. Below 30% sequence identity, Cell/13.html">Protein Structure Data is required to elucidate function. At the same time, it is estimated that 75% of homologous enzymes share less than 30% residue position identity (Todd et al. 2001). Another quantitative study on sequence and function divergence examined the Functional Classification of 6,828 Protein Families within the Gene Ontology framework (Sangar et al. 2007). The study demonstrated that among homologous proteins, The rate of functional divergence drops sharply when sequence identity reaches or exceeds 50%. Nevertheless, even at a sequence identity of 50% or higher, transferring annotations from one homolog to another leads to the misassignment of entirely distinct Functions in 6% of cases.

Andrаs Fiser

Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris

Park Ave, Bronx 10461, NY, USA

e-mail: andras@fiserlab.org, http://www.fiserlab.org

The functional annotation of a protein is greatly facilitated by knowledge of its 3D structure. The insights derived from spatial structures range from low-level functional descriptions, such as confirming fold types (G Wu et al. 2000) and inferring general functional roles, to high-level details like Ligand Specificity and structure-based drug design, including inhibitor discovery (Becker et al. 2006; Evers et al. 2003).