Seminar (chemical biology): Rama Ranaganathan, UT Southwestern Medical Center
Rama Ranaganathan - speaker's webpage
Department of Pharmacology
The Green Center for Systems Biology
University of Texas Southwestern Medical Center
Host: Tom Muir
The Evolutionary "Design" of Proteins
Natural proteins can fold spontaneously into well-defined three-dimensional structures, and can display complex biochemical properties such as signal transmission, efficient catalysis of chemical reactions, specificity in molecular recognition, and allosteric conformational change. All of this is achieved while also preserving the capacity for rapid adaptive variation in response to fluctuating selection pressures, a central feature of evolving systems. What are the basic principles in the "design" of natural proteins that underlie all of these properties? To address this, we developed an approach (the statistical coupling analysis or SCA) for globally estimating the pattern of functional interactions between sites on proteins through statistical analysis of the evolutionary divergence of a protein family1,2. This analysis indicates a novel decomposition of proteins into sparse groups of co-evolving amino acids that we term "protein sectors"9. The sectors are evolutionarily quasi-independent and comprise physically connected networks in the tertiary structure. Experiments in several protein systems demonstrate the functional and adaptive importance of the sectors1,3,4,7,8,10,11,12 and recently, the SCA information was shown to the necessary and sufficient to design functional artificial members of two protein families in the absence of any structural or chemical information5,6. These results support the hypothesis that sectors represent the basic architecture underlying folding, function, and adaptive variation in proteins. We are now working on two key problems: (1) understanding the physical mechanisms underlying sectors, and (2) defining how the dynamics of the evolutionary process controls the emergence and structural architecture of sectors in proteins.
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