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.

在化学系 (CHE) 生命过程化学 (CLP) 项目和刺激竞争性研究既定项目 (EPSCoR) 的支持下，新墨西哥大学的 Yi He 将研究蛋白质相互作用之间的相互作用机制。与 C 激酶-1 (PICK1) 及其结合伙伴一起识别驱动这些过程的关键残基和物理力。 PICK1 是一种信号蛋白，有助于转运细胞蛋白，并与多种疾病有关，包括阿尔茨海默病、帕金森病和可卡因成瘾。该项目旨在利用计算技术和实验验证来研究与PICK1相关的生物过程中涉及的关键步骤，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功能。该项目开发的计算策略还可用于探索原子级相互作用以及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暑期研究课程为 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并促进 STEM 教育，特别是针对农村地区代表性不足的少数族裔和妇女。该项目的研究成果将用于创建基于虚拟现实的推广计划，以提高年轻一代对药物使用障碍（SUD）的认识，并为新墨西哥大学化学和化学生物学课程的开发做出贡献。这项研究该项目旨在利用一种新颖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 二聚体的生物功能相关的域间动力学，以及 3) 关键残基和物理相互作用调节 PICK1 的生物功能相关的结构和机械特性。这一目标最终将通过应用基于物理的先进原子和粗粒度模拟来实现，这些模拟现在可以达到 PICK1 等大型蛋白质的相关时间尺度。该方法有望提供高分辨率模拟数据，以促进我们详细了解 PICK1 的结构和动态特性，最终控制 PICK1 的相互作用机制。总之，该项目旨在利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，并有助于更广泛地了解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，并被认为是值得的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来提供支持。