CAREER: Revealing the interaction mechanisms of PICK1 using multiscale modeling

在化学系（CHE）生命过程化学（CLP）项目和刺激竞争研究既定项目（EPSCoR）的支持下，新墨西哥州大学的Yi He将研究与C激酶1（PICK 1）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力。 PICK 1是一种信号蛋白，有助于运输细胞蛋白，并与各种疾病有关，包括阿尔茨海默氏症，帕金森氏症和可卡因成瘾。该项目旨在使用计算技术和实验验证来研究与PICK 1相关的生物过程中涉及的关键步骤，目的是了解PICK 1的物理相互作用和特定成分如何影响其生物功能。在这个项目中开发的计算策略也可以用来探索原子水平的相互作用和其他大型柔性蛋白质及其复合物的动力学/相互作用。该项目将通过计算研讨会和夏季研究课程为K-12和PUI（主要是本科院校）学生提供研究经验。目标是提高新墨西哥州的学生保留率，促进STEM教育，特别是针对代表性不足的少数民族和农村地区的妇女。本项目的研究成果将用于创建基于虚拟现实的外展计划，以提高年轻一代对物质使用障碍（SUD）的认识，并为&新墨西哥州大学化学化学生物学课程的发展做出贡献。本研究项目旨在利用一种新的计算解决方案来研究1）PICK 1与其结合伙伴的相互作用机制，2）与PICK 1二聚体的生物学功能相关的结构域间动力学，以及3）调节PICK 1的生物学功能相关的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应用基于先进物理的原子和粗粒度模拟来实现，这些模拟现在可以达到PICK 1等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，以促进我们详细了解PICK 1的结构和动力学性质，最终控制PICK 1的相互作用机制。综上所述，该项目旨在利用先进的多尺度计算化学方法对PICK 1的功能机制提供基本的见解，并有助于更广泛地了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价值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.