Physics (Internal)

Evolutionary Design Principles for Cellular Systems

This event is part of the Biophysics/Condensed Matter Seminar Series.

Abstract: Cellular function and fitness depends on the cooperative action of many proteins. Allosteric regulation, the formation of physical complexes, and the organization of enzymes into metabolic cascades represent several ways in which proteins can be functionally coupled to one another to produce useful cellular behaviors. How are such functional interactions between proteins encoded at the amino acid level, and how do they evolve? Statistical analysis of amino acid co-evolution in individual protein domains reveals a general architecture for natural proteins in which sparse networks of amino acids underlie basic aspects of structure and function. These networks, now termed sectors, form physically contiguous pathways embedded in the tertiary structure. Using the metabolic enzyme dihydrofolate reductase (DHFR) as a model system, we show that (1) sector-connected residues on the protein surface are hot spots for the gain of allosteric regulation and (2) the sector of DHFR co-evolves with a second, epistatically coupled metabolic protein. These findings suggest practical guidelines for the engineering of new allosteric systems, permit description of a plausible model for the evolution of intermolecular communication, and motivate a global analysis of evolutionary couplings between proteins in cellular systems.