Mathematical Models of Molecular Motors

分子马达的数学模型

• 批准号: 9972826
• 负责人: George Oster
• 金额: $ 42万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9972826&HistoricalAwards=false
• 关键词: Mathematical; Models; Molecular; Motors

Oster9972826 The investigator and his colleagues continue studies ofbiomolecular motors and mechanochemical phenomena at themicroscale. They focus attention on two particular proteinmotors: ATP synthase and kinesin. The former is a rotary motorthat combines in one protein the two major mechanism of energytransduction: The F1 portion hydrolyzes ATP to generate a rotarytorque, and the Fo portion utilizes the energy stored in atransmembrane electrochemical gradient to generate a rotarytorque in the opposite direction. Kinesin is a molecular motorthat hydrolyzes ATP to generate linear force and displacementalong its microtubule track. Both of these motors have beencharacterized in great detail, mechanically and biochemically aswell as structurally. The challenge is to incorporate thisdiverse body of information into a comprehensive model thatprovides a consistent explanation for each motor's behavior. Theinvestigators have formulated models for both motors comprisingATP synthase. These models contain several phenomenologicalcomponents that must now be modeled at a more detailed level toprovide mechanistic explanations. In particular, the process ofbinding ATP to the catalytic site is the heart of the energytransduction mechanism. They model this process in detail. Thestarting point for the proposed kinesin work is their 1995 model,which is tested against more recent data, such as trajectoryvariance as a function of load (an experiment that theysuggested). The role of elasticity in molecular motor function,which they have demonstrated in the context of imperfect BrownianRatchet motors, is studied in kinesin (which is connected to itsload through a flexible protein linkage), and also in chromosometransport during cell division, in protein translocation acrossintracellular membranes, and in the elastic coupling thatconnects the F1 and Fo motors comprising ATP synthase. Theinfluence of the water environment on the operation of molecularmotors is investigated by developing a newmathematical/computational framework for mesoscale fluiddynamics. This methodology combines a traditional continuumdescription of the fluid with random forces that simulateBrownian motion. They use similar methods to simulateosmotically driven water transport within biological cells. Mathematical modeling and computer simulation of livingsystems is needed in order to make sense out of the vast body ofmultidisciplinary data that is being generated at an everincreasing pace by experimental biologists. Biological cells arenow known to be teeming with protein motors, which, like tinyrobotic machines, conduct the business of life through mechanicalprocesses driven by the expenditure of chemical energy. Themechanisms by which these motors operate are fundamental secretsof nature, vital to the understanding of life itself.Experimental investigations suggest possible mechanisms, but itis only through mathematical modeling and computer simulationthat one can tell whether a proposed mechanism will account, in aquantitative way, for the observed behavior of any particularmolecular motor. The goal of this project is a detailedblueprint for the operating principles of these molecularmachines.

Oster9972826研究员和他的同事们继续在微观尺度上研究生物分子马达和机械力化学现象。他们将注意力集中在两个特定的蛋白质马达上：三磷酸腺苷合成酶和激动素。前者是一种旋转马达，它在一个蛋白质中结合了两种主要的能量传递机制：F1部分水解ATP以产生旋转扭矩，而Fo部分利用储存在跨膜电化学梯度中的能量产生相反方向的旋转扭矩。动蛋白是一种分子马达，它能水解三磷酸腺苷，产生沿其微管轨迹的线性作用力和位移。这两个马达在机械、生化和结构上都有非常详细的特点。挑战是将这些不同的信息体整合到一个全面的模型中，为每个马达的行为提供一致的解释。研究人员已经建立了包括ATP合成酶在内的两个马达的模型。这些模型包含几个现象学组件，现在必须在更详细的水平上进行建模，以提供机械解释。特别是，将ATP结合到催化部位的过程是能量转导机制的核心。他们对这个过程进行了详细的建模。提出的Kinesin工作的起点是他们1995年的模型，该模型根据最近的数据进行了测试，例如作为负载函数的轨迹变化(他们建议的实验)。他们已经在不完善的Brownian Ratchet马达的背景下展示了弹性在分子马达功能中的作用，研究了动蛋白(通过柔性蛋白质连接到其负载)、细胞分裂过程中的染色体运输、跨细胞膜的蛋白质转位以及连接F1和Fo马达的弹性耦合(包括ATP合成酶)。通过发展一种新的介观流体动力学的数学/计算框架，研究了水环境对分子马达运行的影响。这种方法将流体的传统连续描述与模拟布朗运动的随机力相结合。他们使用类似的方法来模拟渗透驱动的水在生物细胞内的运输。为了从实验生物学家正在以越来越快的速度产生的大量多学科数据中获得意义，需要对生命系统进行数学建模和计算机模拟。现在已知的生物细胞中充满了蛋白质马达，就像微小的机器人机器一样，这些马达通过化学能量消耗驱动的机械过程来进行生命活动。这些马达运行的机制是自然界的基本秘密，对理解生命本身至关重要。实验研究提出了可能的机制，但只有通过数学建模和计算机模拟，人们才能知道所提出的机制是否会以定量的方式解释任何特定分子马达的观察到的行为。这个项目的目标是为这些分子机器的工作原理绘制一份详细的蓝图。