Harnessing simulations to uncover molecular mechanisms of mechanosensing

利用模拟揭示机械传感的分子机制

• 批准号: 10727071
• 负责人: Glen Hocky
• 金额: $ 0.7万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727071
• 关键词: Adopted; Behavior; Binding Proteins; Biological Process; Blood flow; Cells; Computer Simulation; Disease; Health; Human; Immune; Mechanics; Methodology; Molecular; Molecular Conformation; Physiological; Play; Process; Protein Conformation; Proteins; Role; Sampling; Techniques; Tissues; Work; behavior change; cancer cell; environmental adaptation; mechanical force; mechanical stimulus; mechanotransduction; response; simulation

Project Summary In order to perform some of their most important functions, cells must be able to generate, sense, and respond to mechanical forces. Many “mechanosensing” proteins have been discovered that are believed to change their behavior in a predictable and repeatable way when under mechanical tension. Yet, in most of these cases, we don’t know the molecular basis of how this force shifts the conformations adopted by the protein, or how this then leads to a concomitant change function. The molecular basis of mechanosensing can in principle be predicted using molecular simulation techniques, however this approach has either not been employed or not been successful because of the small magnitude of forces involved and the large size and complexity of the mechanosensors. In this work, we will develop a set of new simulation methodologies to properly sample protein conformations and protein-ligand biding lifetimes at a range of small forces. We will employ these techniques to study mechanosensing in three different contexts where we believe three distinct mechanisms for changing behavior in response to force are employed. Overall, the work in these studies will lead to a much greater understanding of the molecular paradigms used by cells to regulate their behavior in response to mechanical stimuli, and expand our simulation toolbox to be able to properly sample and assess their response to physiologically small forces.

项目摘要 为了执行其一些最重要的功能，细胞必须能够产生，感知和 响应机械力。已经发现了许多“机械感应”蛋白 在机械张力下，被认为以可预测且可重复的方式改变其行为。 但是，在大多数情况下，我们不知道这种力如何改变的分子基础 蛋白质采用的构象，或者如何导致伴随变化功能。 原理可以使用分子模拟预测机理的分子基础 技术，但是这种方法要么没有被录用，要么没有成功 涉及的力量很小，机械学器的尺寸和复杂性很大。 这项工作，我们将开发一组新的仿真方法来正确采样蛋白质 构象和蛋白质 - 配体屈服寿命在一系列小型力量上。我们将采用这些 在三种不同的情况下研究机械感应的技术，我们相信三个不同的 采用了改变行为的机制，以响应武力。总体而言，这些工作 研究将导致对细胞调节的分子范例有更大的了解 它们响应机械刺激的行为，并扩展我们的仿真工具箱 适当采样并评估他们对物理小部队的反应。

项目成果

Mesoscale molecular assembly is favored by the active, crowded cytoplasm.

活跃、拥挤的细胞质有利于中尺度分子组装。

• DOI: 10.1101/2023.09.19.558334
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Shu,Tong;Mitra,Gaurav;Alberts,Jonathan;Viana,MatheusP;Levy,EmmanuelD;Hocky,GlenM;Holt,LiamJ
• 通讯作者: Holt,LiamJ

Structure of Arp2/3 complex at a branched actin filament junction resolved by single-particle cryo-electron microscopy.

• DOI: 10.1073/pnas.2202723119
• 发表时间: 2022-05-31
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1

Size-and-Shape Space Gaussian Mixture Models for Structural Clustering of Molecular Dynamics Trajectories.

• DOI: 10.1021/acs.jctc.1c01290
• 发表时间: 2022-05-10
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Klem, Heidi;Hocky, Glen M.;McCullagh, Martin
• 通讯作者: McCullagh, Martin

Neural potentials of proteins extrapolate beyond training data.

• DOI: 10.1063/5.0147240
• 发表时间: 2023-08
• 期刊: The Journal of chemical physics
• 作者: Geemi P Wellawatte;Glen M. Hocky;A. White

Molecular Paradigms for Biological Mechanosensing.

• DOI: 10.1021/acs.jpcb.1c06330
• 发表时间: 2021-11-11
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Gomez, David;Ccoa, Willmor J. Pena;Singh, Yuvraj;Rojas, Enrique;Hocky, Glen M.
• 通讯作者: Hocky, Glen M.