CAREER: Variational Bridge between Knowledge-based and Physics-based Models - Applications to Ubiquilin Interactions

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The objective of this CAREER project, jointly funded by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Physics of Living Systems Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, is to develop a physics-based coarse-grained force field that can be widely applicable for modeling proteins and regulation of protein-protein interactions. Although simulation methods that evolve the classical dynamics of atomically detailed models have contributed considerable insight into the structure and equilibrium fluctuations of single proteins, the computational expense of all-atom models limits their application for more complex systems. These limitations have motivated tremendous interest in coarse-grained (CG) models that provide much greater computational efficiency, while still providing a detailed description of protein structure. Many CG models can be broadly categorized as either knowledge-based or physics-based models. Knowledge-based models are empirically developed using statistics compiled from experimentally-determined structures present in the protein databank (PDB). In contrast, physics-based protein models are developed using more rigorous theories and, consequently, hold the potential for greater accuracy. This project bridges the gap between knowledge- and physics-based models by employing a rigorous statistical mechanics framework to develop protein models from PDB structures. This project will first quantify and systematically improve the approximations employed in current knowledge-based methods. These results will guide the development of a highly efficient CG model that accurately describes the structure and interactions for a wide range of proteins. The PI will develop a pioneering intergenerational science club (ISC) to capitalize upon the vastly underused expertise of emeritus faculty to strengthen local intergenerational community, enrich K-12 education in underserved rural Pennsylvania, and promote an active lifestyle of life-long learning. The ISC will be initially developed as series of lectures for local retirees given by emeritus Penn State faculty, but will develop laboratory components and also additional outreach to K-12 students. This program will provide unique intergenerational mentorship for students of all ages and employ discovery-based education to inform the general electorate about the impact of cutting-edge scientific research upon modern society. The Penn State Outreach Office and the Pennsylvania Cooperative Extension will publish and distribute the program further propagating its impact. This project will also develop interdisciplinary physical chemistry curriculum and supplemental lectures to empower chemistry students with the rigorous mathematical and physical tools necessary for addressing the fundamental scientific challenges of the future.