Computational modeling of cytoskeleton-cytoplasm mechanics at the mesoscale

介观尺度细胞骨架-细胞质力学的计算模型

• 批准号: 2052515
• 负责人: Alexander Mogilner
• 金额: $ 30万
• 依托单位: New York University
• 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: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2052515&HistoricalAwards=false
• 关键词: Computational; modeling; cytoskeleton; cytoplasm; mechanics

Cell mechanics is largely determined by the cytoskeleton, which is a dynamic mesh made of semiflexible fibers such as actin filaments, as well as multiple types of cross linking proteins, and molecular motors such as myosin. The fundamental problem addressed in this project is to understand the connections between structure, dynamics, and function of the cytoskeleton. It is not yet known if microscopic filaments can self-organize into the macroscopic chiral structures responsible for left-right asymmetry seen in some tissues, or why networks of actin gels are typically contractile (with or without molecular motors like myosin). The stochastic nature of sub-cellular processes coupled with the ever-changing topology of cytoskeletal networks make these questions difficult or impossible to interrogate through lab measurements or existing simulation techniques. This project will develop computational tools required to close this knowledge gap; tools which carefully capture the microscopic features of cellular fiber networks, at the extraordinary computational scale required to probe their macroscopic structure. The goal is to derive a macroscopic hydrodynamics-like theory from the numerical simulations of the cytoskeletal gels that will allow PI to simulate whole-cell mechanochemical phenomena, like cytokinesis. Education and outreach activities related to this project will include learning modules focused on cell mechanics simulation and biological fluids, implemented in both summer research experience programs for undergraduates and after school programs at New York area middle schools.The goal of this project is to answer five fundamental questions in cellular biology: (1) What are the (hydro)mechanical properties of cross-linked actin networks? (2) Why are actin-myosin gels usually contractile? (3) Can microscopic twists of actin filaments self-organize into macroscopic chiral structures? (4) How much do thermal forces contribute to the viscoelastic gel moduli? (5) Can thermal forces transduce random microscopic twists and bends of actin filaments into macroscopic gel contraction without myosin? To interrogate these questions, the team will develop novel numerical methods which utilize creative representations of fibers to directly enforce their inextensiblity and describe the local twist along their length. The methods will reconcile the hydrodynamics of both passive and active filaments with fluctuations from the surrounding cytosol, in addition to carefully accounting for intra-network dynamics from the motion of molecular motors and dynamically binding/unbinding cross-linkers. The team will employ efficient, iterative linear algebra to compute fiber dynamics in linear time in the number of fibers, enabling unprecedented simulations of the cellular cytoskelton. The team will develop spectrally-accurate Chebyschev discretizations of semi-flexible fibers that dramatically reduce the total degrees of freedom needed to describe a single filament, and implement them in efficient, parallel, public-domain codes.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.

细胞力学在很大程度上取决于细胞骨架，细胞骨架是由半柔性纤维（如肌动蛋白丝）以及多种类型的交联蛋白和分子马达（如肌球蛋白）组成的动态网格。在这个项目中解决的基本问题是了解结构，动力学和细胞骨架的功能之间的联系。目前尚不清楚微观细丝是否可以自组织成宏观手性结构，这些结构导致了某些组织中的左右不对称性，或者为什么肌动蛋白凝胶网络通常是收缩性的（有或没有像肌球蛋白这样的分子马达）。亚细胞过程的随机性加上不断变化的细胞骨架网络拓扑结构，使得这些问题很难或不可能通过实验室测量或现有的模拟技术进行询问。 该项目将开发缩小这一知识差距所需的计算工具;仔细捕捉细胞纤维网络微观特征的工具，以探测其宏观结构所需的非凡计算规模。我们的目标是从细胞骨架凝胶的数值模拟中推导出一个宏观的流体力学理论，这将使PI能够模拟全细胞的机械化学现象，如胞质分裂。与此项目相关的教育和外展活动将包括以细胞力学模拟和生物流体为重点的学习模块，在本科生暑期研究体验项目和纽约地区中学的课后项目中实施。(2)为什么肌动蛋白-肌球蛋白凝胶通常是收缩性的？(3)肌动蛋白丝的微观扭曲能自组织成宏观手性结构吗？(4)热力对粘弹性凝胶模量的影响有多大？(5)热力能将肌动蛋白丝的随机微观扭曲和弯曲转变为没有肌球蛋白的宏观凝胶收缩吗？为了解决这些问题，该团队将开发新的数值方法，利用纤维的创造性表示来直接加强其不可扩展性，并描述沿着其长度的局部扭曲。该方法将调和被动和主动丝与周围的细胞质的波动的流体动力学，除了仔细考虑从分子马达的运动和动态绑定/解除绑定的交联剂的网络内动态。该团队将采用高效的迭代线性代数来计算线性时间内纤维数量的纤维动力学，从而实现对细胞胞浆素的前所未有的模拟。该团队将开发光谱精确的半柔性纤维切比雪夫离散化，大大减少描述单丝所需的总自由度，并在高效，并行，公共领域的代码中实现它们。该奖项反映了NSF的法定使命，并被认为值得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来支持。

项目成果

Bending fluctuations in semiflexible, inextensible, slender filaments in Stokes flow: Toward a spectral discretization

斯托克斯流中半柔性、不可延伸、细长丝的弯曲波动：走向光谱离散化

• DOI: 10.1063/5.0144242
• 发表时间: 2023
• 期刊: The Journal of Chemical Physics
• 作者: Maxian, Ondrej;Sprinkle, Brennan;Donev, Aleksandar
• 通讯作者: Donev, Aleksandar

Computing hydrodynamic interactions in confined doubly periodic geometries in linear time

• DOI: 10.1063/5.0141371
• 发表时间: 2023-04-21
• 期刊: JOURNAL OF CHEMICAL PHYSICS
• 影响因子: 4.4
• 作者: Hashemi, Aref;Pelaez, Raul P.;Donev, Aleksandar
• 通讯作者: Donev, Aleksandar

Slender body theories for rotating filaments

旋转细丝的细长体理论

• DOI: 10.1017/jfm.2022.869
• 发表时间: 2022
• 期刊: Journal of Fluid Mechanics
• 影响因子: 3.7
• 作者: Maxian, Ondrej;Donev, Aleksandar
• 通讯作者: Donev, Aleksandar

Hydrodynamics of a twisting, bending, inextensible fiber in Stokes flow

斯托克斯流中扭转、弯曲、不可拉伸纤维的流体动力学

• DOI: 10.1103/physrevfluids.7.074101
• 发表时间: 2022
• 期刊: Physical Review Fluids
• 影响因子: 2.7
• 作者: Maxian, Ondrej;Sprinkle, Brennan;Peskin, Charles S.;Donev, Aleksandar
• 通讯作者: Donev, Aleksandar

Interplay between Brownian motion and cross-linking controls bundling dynamics in actin networks

布朗运动和交联之间的相互作用控制肌动蛋白网络中的捆绑动力学

• DOI: 10.1016/j.bpj.2022.02.030
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Maxian, Ondrej;Donev, Aleksandar;Mogilner, Alex
• 通讯作者: Mogilner, Alex