RUI: Investigation of the structure and dynamics of type IV pilus filaments using all-atom and coarse-grained molecular dynamics

RUI：利用全原子和粗粒分子动力学研究 IV 型菌毛丝的结构和动力学

• 批准号: 1817670
• 负责人: Joseph Baker
• 金额: $ 26.61万
• 依托单位: The College of New Jersey
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817670&HistoricalAwards=false
• 关键词: RUI; Investigation; structure; dynamics; type

This project will use advanced computational approaches to better understand the biomechanical properties of a protein filament that has applications ranging from bionanotechnology to cell motion and bacterial infection. Bacteria and archaea can adhere to surfaces using long, "sticky" filaments that protrude from their cell membranes called type IV pili (T4P). These filaments, which are made of thousands of copies of a protein called pilin, are incredibly strong, yet simultaneously extremely flexible. For example, a single bacterial T4P filament can support up to 10,000 times a bacterium's body weight, and T4P can be stretched to three times their original length without breaking. This project will use a computational approach known as molecular dynamics simulation to investigate the structure and dynamics of T4P filaments. Using this computational approach, simulated forces will be applied to T4P filaments to probe how they respond to being stretched, which will allow the identification of interactions that provide T4P with their great strength. The insights about T4P that will result from this work will inform applications in bionanotechnology, the role that T4P play in bacterial adhesion and motion, and will expand our general knowledge about protein filaments. Furthermore, this project will provide significant training to undergraduate students in a highly cross-disciplinary area of research at the interface of biology, physics, chemistry, and computer science. It will also develop computational learning modules and incorporate them into the undergraduate science curriculum to train students in the computational methods that are increasingly important in all scientific fields.This project uses a computation/theory-led approach to: (1) investigate the dynamics of T4P filaments from three organisms, N. gonorrhoeae, N. meningitidis, and P. aeruginosa, at the all-atom level of resolution using all-atom molecular dynamics simulation, and (2) develop coarse-grained models to study the structural properties of T4P filaments, including the structural transition that occurs for T4P under external force. This comprehensive, multi scale computational approach will provide insights into the strength and dynamics of T4P across multiple length and time scales relevant to T4P function, and importantly will bridge the gap in knowledge that currently exists between the experimental and theoretical understanding of the biomechanics of T4P filaments. Specifically, all-atom simulations will be used to characterize T4P structural heterogeneity and to identify the most important interactions between pilin subunits for maintaining T4P structural integrity in the initial stages of the polymorphic transition that T4P exhibit under the application of external force. External forces will be applied to T4P using steered molecular dynamics protocols. Additionally, all-atom and coarse-grained simulations will be used in combination to determine important T4P filament properties such as the Young's modulus, persistence length, and torsional rigidity. Finally, coarse-grained simulations of T4P filaments under force will allow for the development of the first model of the fully force-transitioned state of a T4P filament, providing unprecedented molecular-scale insights into how the filament changes shape at the molecular scale. The coarse-grained T4P model developed in this project will act as a starting model for bridging from the atomistic scale to the scale of cellular biology. This project will provide novel insights into T4P biomechanics, aid in the fundamental understanding of the role of T4P in prokaryotes, and improve understanding of the plasticity of helical biopolymers.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.

该项目将使用先进的计算方法来更好地了解蛋白质丝的生物力学特性，该蛋白质丝的应用范围从生物纳米技术到细胞运动和细菌感染。细菌和古细菌可以利用从细胞膜伸出的长“粘性”丝附着在表面，称为 IV 型菌毛 (T4P)。这些细丝由数千个称为菌毛蛋白的蛋白质副本组成，非常坚固，但同时又极其柔韧。例如，单个细菌T4P丝可以支撑细菌体重的10,000倍，并且T4P可以拉伸到原始长度的三倍而不断裂。该项目将使用一种称为分子动力学模拟的计算方法来研究 T4P 丝的结构和动力学。使用这种计算方法，模拟力将应用于 T4P 细丝，以探测它们对拉伸的反应，这将允许识别为 T4P 提供强大强度的相互作用。这项工作产生的关于 T4P 的见解将为生物纳米技术的应用、T4P 在细菌粘附和运动中发挥的作用提供信息，并将扩展我们对蛋白质丝的一般知识。此外，该项目将为本科生提供生物学、物理、化学和计算机科学交叉学科高度跨学科研究领域的重要培训。它还将开发计算学习模块并将其纳入本科科学课程中，以培训学生在所有科学领域中日益重要的计算方法。该项目采用计算/理论主导的方法来：（1）研究使用全原子分子动力学模拟在全原子水平分辨率下来自三种生物体（淋病奈瑟菌、脑膜炎奈瑟菌和铜绿假单胞菌）的 T4P 丝，以及 (2) 开发粗粒度模型来研究其结构特性T4P细丝，包括T4P在外力作用下发生的结构转变。这种全面的多尺度计算方法将深入了解与 T4P 功能相关的多个长度和时间尺度上的 T4P 强度和动态，重要的是，它将弥合目前对 T4P 生物力学的实验和理论理解之间存在的知识差距细丝。具体来说，全原子模拟将用于表征T4P结构异质性，并确定菌毛蛋白亚基之间最重要的相互作用，以在T4P在外力作用下表现出的多态转变的初始阶段维持T4P结构完整性。将使用引导分子动力学方案对 T4P 施加外力。此外，将结合使用全原子和粗粒度模拟来确定重要的 T4P 细丝特性，例如杨氏模量、持久长度和扭转刚度。最后，对受力下的 T4P 细丝进行粗粒度模拟将有助于开发 T4P 细丝完全力转变状态的第一个模型，为细丝如何在分子尺度上改变形状提供前所未有的分子尺度见解。该项目中开发的粗粒度 T4P 模型将作为从原子尺度到细胞生物学尺度的桥梁的起始模型。该项目将为 T4P 生物力学提供新颖的见解，有助于从根本上理解 T4P 在原核生物中的作用，并提高对螺旋生物聚合物可塑性的理解。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。

项目成果

Three structural solutions for bacterial adhesion pilus stability and superelasticity.

• DOI: 10.1016/j.str.2023.03.005
• 发表时间: 2023-05-04
• 期刊: STRUCTURE
• 影响因子: 5.7
• 作者: Doran, Matthew H.;Baker, Joseph L.;Dahlberg, Tobias;Andersson, Magnus;Bullitt, Esther
• 通讯作者: Bullitt, Esther

Unveiling molecular interactions that stabilize bacterial adhesion pili.

• DOI: 10.1016/j.bpj.2022.04.036
• 发表时间: 2022-06-07
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Dahlberg, Tobias;Baker, Joseph L.;Bullitt, Esther;Andersson, Magnus
• 通讯作者: Andersson, Magnus

Theory of Change to Practice: How Experimentalist Teaching Enabled Faculty to Navigate the COVID-19 Disruption

• DOI: 10.1021/acs.jchemed.0c00731
• 发表时间: 2020-09-08
• 期刊: JOURNAL OF CHEMICAL EDUCATION
• 影响因子: 3
• 作者: Chan, Benny C.;Baker, Joseph L.;Triano, Rebecca M.
• 通讯作者: Triano, Rebecca M.