MODELING ACTIN DYNAMICS AS A VISCOELASTIC NETWORK

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的目的是通过确定肌动蛋白聚合产生力的机制来解释真核细胞是如何运动的。为了重建最小的基于肌动蛋白的力产生系统，需要四个组成部分：Arp2/3复合物、肌动蛋白、封盖蛋白和表面上的Arp2/3激活剂。这些成分的生化特性是众所周知的，问题是“这些蛋白质可能以什么方式聚集在一起产生力？”已经产生了多种模型，如亚微观尺度上的弹性；细观尺度上的弹性；丝系、推；和挤压。由于系统是不确定的，我们所拥有的数据不能排除任何模型，也不能区分这些不同机制对运动的相对贡献。那么，下一个关键问题是：“产生观察到的运动所需的系统的关键特性是什么？”例如，是否需要网络弹性？还是聚合的自催化？在这项研究中，通过系统地将肌动蛋白系统的已知特性引入计算机模型，我们将确定这些特性对强制生产的具体要求和贡献。在过去的几个月里，我们已经生成了一个基于蒙特卡罗的模型，模拟了肌动蛋白网络的弹性和压缩特性，并确定介观弹性特性是否单独产生了实验观察到的对称破断和持续力。接下来的步骤是系统地引入系统的已知属性，以唤起观察到的行为光谱，确定它们的重要性和冗余性，并设计和进行实验来验证模型。更新（2006年4月）：该项目的计算方面的第一阶段已接近完成，我已开始撰写该项目的第一篇论文，将在未来几个月内提交。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to explain how eukaryotic cells move by determining the mechanism by which actin polymerization produces force. To reconsitute the minimal actin-based force generation system requires four components: Arp2/3 complex, actin, capping protein and an Arp2/3 activator on the surface to be pushed. The biochemical properties of these components are well known and the question `What are the possible ways these proteins could come together to produce force?' has yielded multiple models e.g.~elasticity on sub-microscopic scale; elasticity on the mesoscopic scale; filament tethering and pushing; and squeezing. Since the system is underdetermined, the data we have does not eliminate any model nor distinguish the relative contributions of these different mechanisms to motility. The next key question, then, is: "What are the critical properties of the system that are required to produce the observed motility?" e.g. is network elasticity required? or autocatalysis of polymerication? In this study, by systematically introducing the known properties of the actin system into a computer model, we will determine the specific requirements and contributions of these properties to force production. In the past few months we have generated a Monte Carlo based model that simulates the elastic and compressive properties of an actin network and determine whether mesoscopic elastic properties alone produce symmetry breaking and sustained force as experimentally observed. The next steps are to systematically introduce known properties of the system to evoke the spectrum of observed behaviour, determine their importance and redundancy, and design and conduct experiments to verify the model. Update (Apr 2006): The first pass of the computational side of the project is close to complete, and I have begun writing the first paper from this project, for submission in the next couple of months.