Molecular Simulations of Biological Active Matter

马里兰大学帕克分校的Garegin Papoian获得了化学系化学理论、模型和计算方法项目的奖励，他开发、优化和应用MEDYAN（活动网络的机械动力学）计算框架，用于模拟化学-力学活性物质。材料研究部的凝聚态物质和材料理论项目也为该奖项做出了贡献。传统的物质状态，如固体、液体和气体，是通过组成分子之间的相互作用而自我组织起来的。另一方面，活性物质是由外部能量驱动的自组装产生的。由于化学和力学的强内在耦合，这种系统的建模具有挑战性。活性物质已成为化学、材料物理学和生物学的交叉领域，成为科学研究的新前沿。事实上，人体内的细胞可以被看作是一种高度复杂的活性物质，其外部能量来源于食物。在每个细胞内，相互作用的分子马达、自组装细丝、细胞膜和细胞器的精细相互作用不断地将化学能转化为决定细胞形状、运动和对细胞外环境的感知的力。通过开发和应用MEDYAN软件框架，Papoian的团队正致力于通过整合细胞组成化学、机械和运输过程的新模型，为个体细胞的所有异常复杂性建模，这是一个巨大的挑战。因此，MEDYAN使人们对细胞活性物质的分子原理有了新的认识。作为该项目的一部分，MEDYAN被用于研究神经元中树突棘的自组装和结构稳定性，树突棘支持大脑长期记忆的形成，以及细胞形状振荡，其起源和生物学作用尚不清楚。该软件不仅可以应用于细胞生物学，还可以应用于生物材料，有望促进国民健康。MEDYAN作为开源软件向公众开放，作为项目的一部分，一个活动社区网站和学习资源正在开发中。研究与教育和推广相结合，通过将高中生纳入实验室研究，并不断努力扩大大学化学物理项目申请者的多样性。该项目正在扩展MEDYAN以支持真核细胞建模的基本组成部分。其中包括一个可变形的、化学活性的质膜模型，用二维网格和相关的Voronoi多边形表示；结合自由能惩罚的面内和面外膜变形；细胞骨架细丝与局部膜斑块的立体和系留相互作用由于渗透压或与体积守恒有关的体积力；以及膜结合蛋白的反应扩散，包括一些蛋白诱导自发膜弯曲的能力。这些进展被进一步用于制定内部细胞器（如细胞核）的计算模型。此外，正在构建一个模型来描述谱蛋白的自组装成一个动态重新排列的二维薄片，短暂地拴在质膜下面。为了达到在生物相关的长度和时间尺度上模拟所需的计算效率，MEDYAN正在最先进的CPU和GPU架构上并行化。这些新的建模和模拟能力正被用于研究细胞生物学中的两个重要问题：树突棘结构稳定性的分子基础，这是动物长期记忆稳定性的基础；集体振荡周期，作为一个迁移锋从一个细胞传播到另一个细胞，这是基于一种叫做脉冲性的细胞骨架现象。对于这两个项目，在迭代模型开发和验证上都有与实验学家的密切合作。下一代MEDYAN为集成有源和非有源组件的可编程物质提供了重要的新建模功能，以实现具有独特性能的智能材料。MEDYAN软件和文档作为开源免费传播。作为该项目的一部分，Papoian博士正在创建一个以活性物质为中心的社区网络资源，为中学、本科和研究生课程提供课堂教学材料，并将与活性物质相关的出版物和在该领域工作的科学团体的信息汇集在一起。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Garegin Papoian of the University of Maryland College Park is supported by an award from the Chemical Theory, Models, and Computational Methods Program in the Division of Chemistry to develop, optimize, and apply the MEDYAN (MEchanical DYnamics of Active Networks) computational framework for modeling chemomechanical active matter. The Condensed Matter and Materials Theory Program in the Division of Materials Research also contributes to this award. Traditional states of matter, such as solids, liquids, and gases, self-organize through interactions among constituent molecules. Active matter, on the other hand, arises from external energy-driven self-assembly. Such systems are challenging to model due to the strong intrinsic coupling of chemistry and mechanics. Active matter has emerged as a new frontier in science, at the interface of chemistry, materials physics, and biology. In fact, the cells in one's body can be viewed as a form of highly complex active matter, where the external energy is derived from food. Within each cell, an elaborate interplay of interacting molecular motors, self-assembling filaments, the cell membrane, and organelles continuously convert chemical energy into forces that determine cellular shape, motility, and sensing of the extracellular environment. Papoian's group, by developing and applying the MEDYAN software framework, is working toward the grand challenge of modeling individual cells in all of their extraordinary complexity, by incorporating new models of the cell's constituent chemical, mechanical, and transport processes. MEDYAN is thus enabling critical new understanding of the molecular principles underlying cellular active matter. As part of this project, MEDYAN is being used to study self-assembly and structural stability of dendritic spines in neurons, which support formation of long-term memories in the brain, and cell shape oscillations, whose origin and biological role are not well understood. The software has applications to biomaterials as well as to cell biology and is expected to advance the national health. MEDYAN is being made available to the public as open source software, and an active matter community website and learning resource is being developed as part of the project. Research is coupled with education and outreach through inclusion of high school students in lab research, and ongoing efforts to expand diversity in applicants within the university's chemical physics program.This project is extending MEDYAN to support essential components of eukaryotic cell modeling. These include a deformable, chemically-active plasma membrane model expressed in terms of a 2D mesh and associated Voronoi polygons; incorporation of a free energy penalty for in-plane and out-of-plane membrane deformations; steric and tethering interactions of cytoskeletal filaments with local membrane patches; volumetric forces due to osmotic pressure or associated with the volume conservation; and reaction-diffusion of membrane bound proteins, including the ability of some proteins to induce spontaneous membrane curvature. These advances are further leveraged to formulate computational models for internal organelles such as the cell nucleus. In addition, a model is being constructed to describe self-assembly of spectrin proteins into a dynamically rearranging 2D sheet transiently tethered underneath the plasma membrane. To achieve the computational efficiency needed for simulating at biologically-relevant length- and timescales, MEDYAN is being parallelized on state-of-the-art CPU and GPU architectures. These new modeling and simulation capabilities are being used to study two important problems in cell biology: the molecular underpinnings of the structural stability of dendritic spines, which underlie the stability of long-term memories in animals; and collective oscillatory cycles, propagating as a migrating front from one cell to another, which are based on a cytoskeletal phenomenon called pulsatility. For both of these projects, there is close collaboration with an experimentalist on iterative model development and validation. This next generation of MEDYAN is providing important new modeling capabilities with applications to programmable matter integrating active and non-active components to achieve smart materials with unique properties. The MEDYAN software and documentation are freely disseminated as open source. As part of this project, Dr. Papoian is creating a community web resource centered around active matter, with class-ready educational materials for secondary schools, undergraduate and graduate courses, and research sections bringing together information on publications relating to active matter and the scientific groups working in the field.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.