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

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。在该项目中，新墨西哥大学（UNM）的何毅教授和他的学生将使用计算方法研究PICK1的结构和力学特性，PICK1是一种生物分子，在包括乳腺癌、精神分裂症、成瘾和成瘾复发在内的许多疾病中发挥作用。何教授还计划扩大参与活动，他们将强调PICK1作为治疗药物使用障碍的潜在药物靶点的效用，并将其作为推广框架。他们将让新墨西哥大学的学生参与研究，开展活动，促进不同教育水平的学生（包括新墨西哥大学的本科生和研究生，这是一所少数民族服务机构，MSI）的融合，并参与区域主要本科机构和高中的外展活动。何教授将通过计算探索与PICK1（与C激酶-1相互作用的蛋白）的生物学功能直接相关的每个子结构域的结构和力学特性相关的关键残基和物理相互作用。计算工具将用于探测PICK1的两个关键分子结构域，PDZ和BAR。他还将优化基于UNRES物理的粗粒度力场，探索连接PDZ和BAR结构域的无序连接子。了解每个子结构域的生物学作用将为探索自然界如何通过模块结构域组装信号蛋白奠定基础。这些目标最终将通过基于先进物理的原子和粗粒度模拟的应用来实现，现在可以达到小蛋白质的相关时间尺度。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.