An algorithm for discovering steric influences on protein-ligand binding specificity

GRAND Seminar October 11, noon, Wed., 2011, ENGR 4201

Brian Chen
http://www.cse.lehigh.edu/~chen/
Assistant Professor
Dept. of Computer Science and Engineering
Lehigh University

Abstract:

Living things are composed of interacting and nested systems that exhibit symptoms of health and disease at all levels. At the most fundamental level, understanding the correct behavior of healthy systems, and resolving the breakdowns that occur in disease, requires a precise understanding of how proteins function and malfunction. Building such an understanding is much like the examination of a complex machine: the analysis of protein shape can yield many insights, especially at functional sites, where biochemical activity actually occurs.

Many algorithms have been designed to gather structural observations, especially about the functional site, that point to functional hypotheses that can be ultimately tested on the bench. In every case, these methods employ a "guilt by association" approach by assigning biological function based on functional site similarity or a resemblance to established norms. This talk asserts that more informative approaches are possible and presents VASP, a new method that dissects functional sites to isolate individual components that play influential functional roles. VASP enables these new capabilities by exploiting a novel connection to concepts from computer graphics and computer aided design.

The results presented in this talk describe a case study where VASP was applied to the analysis of the major serine proteases. VASP isolated individual amino acids and regions of functional sites that enable the serine proteases to preferentially bind specific molecules. None of these observations are possible with existing unsupervised methods. These results point to applications in molecular bioengineering, where the identification of individual functional components is essential for the rational engineering of active biomolecules, and to applications in structure-based drug design, where important functional components could be exploited to mitigate side effects or evade drug resistance.