Computational modeling of cytoskeleton-cytoplasm mechanics at the mesoscale

细胞力学在很大程度上由细胞骨架决定，细胞骨架是由肌动蛋白细丝等半柔性纤维以及多种类型的交联蛋白和肌球蛋白等分子马达组成的动态网状结构。这个项目解决的基本问题是了解细胞骨架的结构、动力学和功能之间的联系。目前尚不清楚微观细丝是否可以自组织成宏观的手性结构，这是某些组织中出现的左右不对称的原因，也不清楚为什么肌动蛋白凝胶网络通常是可收缩的(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细胞骨架网络不断变化的拓扑结构，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来询问。该项目将开发缩小这一知识鸿沟所需的计算工具；这些工具可以在探索其宏观结构所需的非凡计算规模下，仔细捕获蜂窝光纤网络的微观特征。我们的目标是从细胞骨架凝胶的数值模拟中推导出一个类似宏观流体力学的理论，使PI能够模拟整个细胞的机械力化学现象，如胞质分裂。与该项目有关的教育和外联活动将包括侧重于细胞力学模拟和生物流体的学习单元，这个项目的目的是回答细胞生物学中的五个基本问题：(1)交叉连接的肌动蛋白网络的(水)力学性质是什么？(2)为什么肌动蛋白凝胶通常是收缩的？(3)肌动蛋白细丝的微观缠绕能否自组织成宏观的手性结构？(4)热力对粘弹性凝胶模数有多大贡献？(5)热力能否将肌动蛋白细丝的随机微观扭曲和弯曲转化为宏观凝胶收缩而没有肌球蛋白？为了回答这些问题，该团队将开发新的数值方法，利用纤维的创造性表示法直接加强纤维的不可延展性，并描述沿纤维长度的局部扭曲。这些方法将使被动和主动细丝的流体动力学与周围胞浆的波动相协调，此外，还将仔细考虑分子马达运动和动态结合/解除结合交联剂的网络内动力学。该团队将使用高效的迭代线性代数来计算纤维数量的线性时间内的纤维动力学，从而实现对细胞胞质的前所未有的模拟。该团队将开发光谱精确的半柔性纤维切比雪夫离散化方法，大大减少描述单个纤维所需的总自由度，并以高效、并行、公共领域的代码实施。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.