CAREER: Revealing the interaction mechanisms of PICK1 using multiscale modeling

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With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry (CHE), and the Established Program to Stimulate Competitive Research (EPSCoR), Yi He of the University of New Mexico will investigate the interaction mechanisms between Protein Interacting with C Kinase-1 (PICK1) and its binding partners to identify the key residues and physical forces that drive these processes. PICK1 is a signaling protein that helps transport cellular proteins and has been linked to various diseases including Alzheimer's, Parkinson's, and addiction to cocaine. This project aims to use computational techniques and experimental validation to investigate the key steps involved in biological processes related to PICK1, with the goal of understanding how physical interactions and specific components of PICK1 influence its biological functions. The computational strategy developed in this project can also be used to explore the atomic-level interactions and the dynamics/interactions of other large flexible proteins and their complexes. This project will provide K-12 and PUI (primarily undergraduate institution) students with research experience through computational workshops and summer research sessions. The goal is to increase student retention rates in New Mexico and promote STEM education, especially for underrepresented minorities and women in rural areas. The research outcomes of this project will be used to create Virtual Reality based outreach programs to raise awareness of Substance Use Disorders (SUD) among younger generations and contribute to the development of the Chemistry & Chemical Biology curriculum at the University of New Mexico.This research project aims to utilize a novel computational solution to investigate 1) the interaction mechanisms of PICK1 with its binding partners, 2) the inter-domain dynamics associated with the biological functions of the PICK1 dimer, and 3) the key residues and physical interactions that regulate the biological function related structural and mechanical properties of PICK1. This goal is to ultimately be achieved by the application of advanced physics-based atomistic and coarse-grained simulations, which can now reach relevant timescales for large proteins such as PICK1. This approach is expected provide high-resolution simulation data to facilitate our detailed understanding of the structural and dynamic properties of PICK1 that ultimately control the interaction mechanisms of PICK1. In summary, this project seeks to use advanced multiscale computational chemistry methods to provide fundamental insights into the functional mechanism of PICK1 and contribute to the broader understanding of signal transduction mediated by such signaling 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.