Fine tuning of protein functional atomistic dynamics in molecular evolution and cellular processes

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Proteins are one of the basic cellular building blocks and are essential for carrying out processes inside cells. The findings of this research will provide new basic understanding of how the movement or dynamics of proteins and their interactions of other molecules affects protein function. Better understanding of protein function could help in the design of new protein catalysts for biotechnology applications and well as lead to a greater understanding of how protein disfunction contributes to disease. The research will also produce new computational tools, including new software, that will assist others in their research and in developing new technology. The research cuts across many disciplines, including chemistry, biology, physics, mathematics, and computer science, and provides an excellent opportunity to train students at all levels. More specifically, the research will have a broader impact on the scientific training of students at Georgia State University, with focus on better preparing underrepresented minority students for graduate school. Georgia State University is the largest and most diverse research-intensive university in Georgia, providing a unique opportunity to engage a diverse student body and underrepresented minority groups in science and engineering. Students will be equipped with research experiences, fundamental knowledge, and professional skills that are required to successfully transition to doctoral programs in chemical and biomedical sciences. Additionally, the project will provide outreach to a larger community through well-established programs at Georgia State University.Protein conformational motions direct molecular recognition, enzyme catalysis, and allosteric regulation in many cellular processes. Conformational dynamics underlies the fine tuning of many cellular processes, including transient protein-protein interactions, signal transduction, and gene regulation in response to biochemical processes and changes in cellular conditions. Deregulation of the dynamics controlling one or more of these processes can lead to aberrant cellular function. Despite intensive studies on elucidating the complex structure-dynamics-function relationship, how protein function has evolved and is regulated remain poorly understood. The goal of the research is to establish the dynamical link for controllable modulations of function in proteins using large-scale computer simulations performed under distinct substrate-binding and sequence conditions. Specifically, the research will determine how various modifications of protein function, including gain and loss of catalytic activity, are achieved through evolution in the family of human cyclophilins and establish a complete model of the sequence dependent allosteric mechanism in human Pin1. Additionally, innovative and efficient computational methods will be developed to identify key allosteric residues in proteins from large simulation data. General principles of how allosteric signals microscopically propagate within a network of protein residue-residue interactions will be obtained, complementing the well-established thermodynamic models for macroscopic understanding of allosteric regulation. The research will provide deep insights into the role of protein dynamics in recognition, catalysis, and allosteric regulation in cellular processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.