CAREER: Cellular Mechanics at the Nanoscale: Lipid Membrane Elasticity and Force Transduction in Mechanosensitive Proteins

职业：纳米尺度的细胞力学：机械敏感蛋白中的脂质膜弹性和力传导

• 批准号: 1944892
• 负责人: Juan Vanegas
• 金额: $ 63.51万
• 依托单位: University of Vermont & State Agricultural College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1944892&HistoricalAwards=false
• 关键词: CAREER; Cellular; Mechanics; Nanoscale; Lipid

Juan M. Vanegas of The University of Vermont & State Agricultural College is jointly funded by the the Chemical Theory, Models and Computational Methods (CTMC) program in the Division of Chemistry and the Established Program to Stimulate Competitive Research (EPSCoR) to characterize the mechanical behavior and response of cellular components to physical stimuli at the nanometer scale through novel computational methods. Professor Vanegas develops state of the art computational tools to investigate two fundamental questions in the area of nano-scale biomechanics. The first question is "What is the role of fat (lipid) structure in a model biomembrane?" The second question is, "How does a protein sense external physical stimuli such as pressure?" Answering these questions is essential to understanding how biological systems function during membrane fission and fusion, organelle and cellular shaping, cardiovascular control and development, osmotic regulation, and touch and pain sensing. The open-source computational tools and methods developed by Professor Vanegas’ group are enabling a broad range of studies on other areas of biochemistry, biophysics, and materials science. The educational component of this CAREER proposal focuses on transitioning introductory physics courses at the University of Vermont to an active learning studio/workshop environment designed to significantly improve understanding of core concepts and increasing participation from women and underrepresented minorities. Professor Vanegas is also actively participating in student recruitment and developing new curriculum to support the newly-established Ph.D. program in physics at the University of Vermont. Mechanics of biomembranes and mechanosensitive channels are investigated through the development and application of state of the art molecular simulation tools in steered molecular dynamics and local stress/elasticity calculations. This CAREER proposal by Professor Juan M. Vanegas pivots around two independent yet highly complementary research objectives aimed at understanding the connection between the molecular structure of biomolecules such as lipids and membrane proteins and mechanically-coupled, biological functions. The research component focuses on two main tasks. These include the direct estimation of local and macroscopic elastic moduli from molecular dynamics simulations, and force transduction and energetics of gating in mechanosensitive proteins through non-equilibrium simulations. Professor Vanegas is developing innovative computational methods to capture mechanical properties from molecular models through calculation of the microscopic stress and elasticity tensors which measure the local balance of forces and elastic response within a material. These continuum-like fields provide a unique connection between molecular structure, mechanical properties at the nanoscale, and large scale mechanical behaviors. Complimentary steered simulation methods developed by Vanegas further allow efficient exploration of mechanically-driven biological processes in mechanosensitive channels to establish a general framework for their function.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.

佛蒙特大学和州立农业学院的 Juan M. Vanegas 受到化学系化学理论、模型和计算方法 (CTMC) 项目和刺激竞争性研究既定项目 (EPSCoR) 的联合资助，以表征机械行为Vanegas 教授开发了最先进的计算工具来研究纳米级生物力学领域的两个基本问题。第一个问题是“脂肪（脂质）结构在模型生物膜中的作用是什么？”第二个问题是“蛋白质如何感知压力等外部物理刺激？” Vanegas 教授团队开发的开源计算工具和方法正在促进其他领域的广泛研究。的该职业提案的教育部分侧重于将佛蒙特大学的入门物理课程转变为积极的学习工作室/研讨会环境，旨在显着提高对核心概念的理解并增加女性和代表性不足的少数族裔的参与。 Vanegas 教授还积极参与学生招募和开发新课程，以支持佛蒙特大学新设立的物理学博士项目，研究生物膜和机械敏感通道。 Juan M. Vanegas 教授的这项职业提案围绕两个独立但高度互补的研究目标，旨在了解分子之间的联系。研究部分重点关注脂质和膜蛋白等生物分子的结构以及机械耦合的生物功能，其中包括通过分子动力学模拟直接估计局部和宏观弹性模量，以及力传导和能量学。 Vanegas 教授正在开发创新的计算方法，通过计算微观应力和弹性张量来捕获材料中力的局部平衡和弹性响应，从而从分子模型中捕获机械特性。类似的场在分子结构、纳米级机械性能和大规模机械行为之间提供了独特的联系，Vanegas 开发的互补引导模拟方法进一步允许有效探索机械敏感的机械驱动生物过程。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。

项目成果

Balance of Solvent and Chain Interactions Determines the Local Stress State of Simulated Membranes

溶剂和链相互作用的平衡决定模拟膜的局部应力状态

• DOI: 10.1021/acs.jpcb.0c03937
• 发表时间: 2020-08
• 期刊: The Journal of Physical Chemistry B
• 作者: Winkeljohn, Conner M.;Himberg, Benjamin;Vanegas, Juan M.
• 通讯作者: Vanegas, Juan M.

Mechanical Activation of MscL Revealed by a Locally Distributed Tension Molecular Dynamics Approach

局部分布张力分子动力学方法揭示了 MscL 的机械激活

• DOI: 10.1016/j.bpj.2020.11.2274
• 发表时间: 2021-01
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Rajeshwar T., Rajitha;Anishkin, Andriy;Sukharev, Sergei;Vanegas, Juan M.
• 通讯作者: Vanegas, Juan M.

Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor

膜介导的机械刺激在 AT1 受体中产生独特的活性样状态

• DOI: 10.1038/s41467-023-40433-4
• 发表时间: 2023-08
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Poudel, Bharat;Rajeshwar T, Rajitha;Vanegas, Juan M.
• 通讯作者: Vanegas, Juan M.

Effect of Local Stress on Accurate Modeling of Bacterial Outer Membranes Using All-Atom Molecular Dynamics

局部应力对利用全原子分子动力学精确建模细菌外膜的影响

• DOI: 10.1021/acs.jctc.2c01026
• 发表时间: 2023-01
• 期刊: Journal of Chemical Theory and Computation
• 影响因子: 5.5
• 作者: Pirhadi, Emad;Vanegas, Juan M.;Farin, Mithila;Schertzer, Jeffrey W.;Yong, Xin
• 通讯作者: Yong, Xin

Tight hydrophobic core and flexible helices yield MscL with a high tension gating threshold and a membrane area mechanical strain buffer

紧密的疏水核心和灵活的螺旋产生具有高张力门控阈值和膜区域机械应变缓冲的 MscL

• DOI: 10.3389/fchem.2023.1159032
• 发表时间: 2023
• 期刊: Frontiers in Chemistry
• 影响因子: 5.5
• 作者: Sharma, Arjun;Anishkin, Andriy;Sukharev, Sergei;Vanegas, Juan M.
• 通讯作者: Vanegas, Juan M.