CAREER: Revealing the interaction mechanisms of PICK1 using multiscale modeling

在化学系生命过程化学(CLP)计划和已建立的促进竞争研究计划(EPSCoR)的支持下，新墨西哥大学的毅赫将研究与C激酶-1(PICK1)相互作用的蛋白质及其结合伙伴之间的相互作用机制，以确定驱动这些过程的关键残基和物理作用力。PICK1是一种信号蛋白，帮助运输细胞蛋白，与多种疾病有关，包括阿尔茨海默氏症、帕金森氏症和可卡因成瘾。该项目旨在利用计算技术和实验验证来研究与PICK1相关的生物过程中的关键步骤，目的是了解PICK1的物理相互作用和特定成分如何影响其生物学功能。这个项目中开发的计算策略也可以用于探索其他大型柔性蛋白质及其复合体的原子水平相互作用和动力学/相互作用。这个项目将通过计算工作坊和暑期研究课程为K-12和PUI(主要是本科生)的学生提供研究经验。其目标是提高新墨西哥州的学生保留率，促进STEM教育，特别是针对农村地区代表性不足的少数民族和妇女。该项目的研究成果将用于创建基于虚拟现实的推广项目，以提高年轻一代对物质使用障碍(SUD)的认识，并为新墨西哥大学化学与化学生物学课程的开发做出贡献。该研究项目旨在利用一种新的计算解决方案来研究1)PICK1与其结合伙伴的相互作用机制，2)与PICK1二聚体生物功能相关的域间动力学，以及3)调节PICK1生物功能相关结构和机械性质的关键残基和物理相互作用。这一目标最终将通过先进的基于物理的原子化和粗粒度模拟的应用来实现，现在可以达到像PICK1这样的大型蛋白质的相关时间尺度。这种方法有望提供高分辨率的模拟数据，以帮助我们详细了解PICK1的结构和动力学性质，最终控制PICK1的相互作用机制。总之，这个项目寻求使用先进的多尺度计算化学方法来提供对PICK1功能机制的基本见解，并有助于更广泛地理解由此类信号蛋白介导的信号转导。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.