CAREER: Computational Modeling of Protein Evolvability

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While it is recognized that the molecular evolution of proteins is integral to the evolution of species, the physical mechanisms underlying protein evolution and the physical properties of proteins that facilitate evolution are not well understood. The objective of this CAREER project is to address these questions through the development and application of new theoretical models that rapidly and accurately capture the essential physics and chemistry relevant to the evolution of enzyme function. The approach will specifically involve modeling the effects of mutations on the stability of a native protein fold as well as the effects of mutation on catalytic efficiency. The application of these and other theoretical tools to informative model systems will form the basis for discovering physical-chemical features associated with molecular evolution. Examples of these features include the physical mechanisms underlying compensatory mutations as well as the role of protein stability and dynamics in facilitating transitions to new enzymatic activities.This CAREER project represents an integrated and multidisciplinary educational and research approach, focused on using the laws of chemistry and physics to explain and predict fundamental evolutionary processes in biology. The new methods and new physical understanding of molecular evolution resulting from this project will have direct implications for a variety of fields including protein engineering and design, directed evolution, and nanotechnology. In addition to the impact of the research, the educational goals will impact future scientists by training undergraduate and graduate students to approach biological questions from a quantitative perspective. This objective will be partially realized through the development of a new undergraduate course in chemical biology and a new graduate level course in biophysical chemistry. In addition, this project will involve the development of a new interactive software package that will further establish, for students, the value of applying quantitative thinking to biological questions. The software will do this by allowing students to explore the connection between the physical properties of proteins and the biological function of proteins. The developed educational software will have a broad impact as it will be distributed freely to the public and will therefore be available to universities nationally and internationally.