LEAPS-MPS:Revealing Key Residues and Physical Interactions Drive the Structural and Dynamic Changes in Subdomains of PICK1

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This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). In this project, funded by the Mathematical and Physical Sciences Directorate and housed in the Chemistry Division, Professor Yi He and their students at the University of New Mexico (UNM) will use computational methods to study the structural and mechanical properties of PICK1, a biomolecule that plays a role in a large number of diseases, including breast cancer, schizophrenia, addiction, and addiction relapse. Prof. He also plans broadening participation activities in which they would emphasize the utility of PICK1 as a potential drug target to treat substance use disorder as a framework for outreach. They will involve URM students in research, develop activities that will facilitate integration of students across educational levels (including undergraduate and graduate students at UNM, which is a minority serving institution, MSI), and participate in outreach activities at regional primarily undergraduate institutions and high schools.Professor He will computationally probe the key residues and physical interactions associated with the structural and mechanical properties of each subdomain that is directly related to the biological function of PICK1 (Protein Interacting with C Kinase-1). Computational tools will be used to probe two key molecular domains of PICK1, PDZ and BAR. Prof. He will also optimize the United-RESidue (UNRES) physics-based coarse-grained force field to explore the disordered linker which connects the PDZ and BAR domain. Understanding the biological role of each subdomain will lay the foundation to explore how nature assembles signaling proteins through modular domains. These goals will ultimately be achieved by applications of advanced physics-based atomistic and coarse-grained simulations, which can now reach the relevant timescales for small proteins.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.