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

LEAPS-MPS：揭示关键残基和物理相互作用驱动PICK1子域的结构和动态变化

• 批准号: 2137558
• 负责人: Yi He
• 金额: $ 24.62万
• 依托单位: University of New Mexico
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2137558&HistoricalAwards=false
• 关键词: LEAPS; MPS; Revealing; Key; Residues

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.

该奖项的全部或部分资金根据《2021 年美国救援计划法案》（公法 117-2）提供。 在这个由数学和物理科学理事会资助并设在化学部的项目中，新墨西哥大学 (UNM) 的 Yi He 教授和他们的学生将使用计算方法来研究 PICK1（一种生物分子）的结构和机械特性。它在许多疾病中发挥着作用，包括乳腺癌、精神分裂症、成瘾和成瘾复发。 何教授还计划扩大参与活动，在活动中他们将强调 PICK1 作为治疗药物滥用障碍的潜在药物靶点的效用，并以此作为外展框架。 他们将让 URM 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，MSI 是一个少数族裔服务机构）的融合，并参与地区主要本科院校和高等院校的外展活动。何教授将通过计算探究与PICK1（Protein Interacting with C Kinase-1）的生物学功能直接相关的每个子域的结构和机械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 的两个关键分子域：PDZ 和 BAR。 何教授还将优化United-RESidue（UNRES）基于物理的粗粒度力场，以探索连接PDZ和BAR域的无序连接器。 了解每个子结构域的生物学作用将为探索大自然如何通过模块化结构域组装信号蛋白奠定基础。这些目标最终将通过应用先进的基于物理的原子和粗粒度模拟来实现，这些模拟现在可以达到小蛋白质的相关时间尺度。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力评估进行评估，被认为值得支持。优点和更广泛的影响审查标准。

项目成果

Simple and Effective Conformational Sampling Strategy for Intrinsically Disordered Proteins Using the UNRES Web Server

使用 UNRES Web 服务器对本质无序蛋白质进行简单有效的构象采样策略

• DOI: 10.1021/acs.jpcb.2c08945
• 发表时间: 2023-03
• 期刊: The Journal of Physical Chemistry B
• 作者: Li, Tongtong;Hendrix, Emily;He, Yi
• 通讯作者: He, Yi

Benchmarking the Accuracy of AlphaFold 2 in Loop Structure Prediction

对 AlphaFold 2 在循环结构预测中的准确性进行基准测试

• DOI: 10.3390/biom12070985
• 发表时间: 2022-07-14
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Stevens, Amy O.;He, Yi
• 通讯作者: He, Yi

Allosterism in the PDZ Family

PDZ 家族的变构现象

• DOI: 10.3390/ijms23031454
• 发表时间: 2022-01-27
• 期刊: International Journal of Molecular Sciences
• 影响因子: 5.6
• 作者: Stevens AO;He Y
• 通讯作者: He Y

Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all‐atom simulations

通过全原子模拟研究 PICK1 PDZ 结构域对不同配体的变构反应

• DOI: 10.1002/pro.4474
• 发表时间: 2022-12
• 期刊: Protein Science
• 影响因子: 8
• 作者: Stevens, Amy O.;Kazan, I. Can;Ozkan, Banu;He, Yi
• 通讯作者: He, Yi

Three Binding Conformations of BIO124 in the Pocket of the PICK1 PDZ Domain

PICK1 PDZ 域口袋中 BIO124 的三种结合构象

• DOI: 10.3390/cells11152451
• 发表时间: 2022-08-07
• 期刊: Cells
• 影响因子: 6
• 作者: Amy O. Stevens;Samuel Luo;Yi He
• 通讯作者: Yi He