CAREER: Revealing the interaction mechanisms of PICK1 using multiscale modeling

职业：使用多尺度建模揭示 PICK1 的相互作用机制

• 批准号: 2237369
• 负责人: Yi He
• 金额: $ 50.04万
• 依托单位: University of New Mexico
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-11-01 至 2028-10-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2237369&HistoricalAwards=false
• 关键词: CAREER; Revealing; interaction; mechanisms; PICK1

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.

在化学过程的化学过程（CLP）计划（CHE）和刺激竞争性研究的既定计划（EPSCOR）的支持下，新墨西哥大学的YI HE将研究与C激酶-1（Pick1）相互作用的蛋白质之间的相互作用机制（PICK1）及其结合零件，以确定键入这些过程的键值和物理力。 Pick1是一种信号蛋白，可帮助运输细胞蛋白，并与包括阿尔茨海默氏症，帕金森氏症和可卡因成瘾在内的各种疾病有关。该项目旨在使用计算技术和实验验证来研究与Pick1相关的生物过程中涉及的关键步骤，以了解物理相互作用和PICK1的特定组成部分如何影响其生物学功能。该项目中开发的计算策略也可用于探索其他大型柔性蛋白及其复合物的原子级相互作用以及动态/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（主要是本科机构）学生提供研究经验。目的是提高新墨西哥州的学生保留率并促进STEM教育，尤其是对于农村地区代表性不足的少数民族和妇女而言。该项目的研究结果将用于创建基于虚拟现实的外展计划，以提高年轻一代中的物质使用障碍（SUD）的认识，并为新墨西哥大学的化学和化学生物学课程的发展做出贡献。本研究项目的旨在利用一种新颖的计算解决方案来调查其与访问的互动机构的相关性。 Pick1二聚体，以及3）调节生物学功能相关的结构和机械性能的关键残基和物理相互作用。该目标最终是通过应用基于高级物理学的原子和粗粒的模拟来实现的，该模拟现在可以达到大型蛋白质（如Pick1）的相关时间表。预计这种方法可提供高分辨率仿真数据，以促进我们对PICK1的结构和动态特性的详细理解，这些属性最终控制了PICK1的相互作用机理。 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.