Mathematical Models of Molecular Motors

[ster9972826]研究者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化学现象。他们把注意力集中在两种特殊的蛋白质马达上：ATP合成酶和运动蛋白。前者是一个旋转马达，在一个蛋白质中结合了两种主要的能量转导机制：F1部分水解ATP产生旋转扭矩，Fo部分利用跨膜电化学梯度中储存的能量产生相反方向的旋转扭矩。运动蛋白是一种分子马达，它水解ATP以沿着微管轨迹产生线性力和位移。这两种马达都有非常详细的特征，机械和生物化学以及结构。挑战在于将这些不同的信息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。研究人员已经为这两种包含atp合酶的马达制定了模型。这些模型包含几个现象学成分，现在必须在更详细的层面上进行建模，以提供机制解释。特别是，ATP结合到催化位点的过程是能量转导机制的核心。他们详细地模拟了这一过程。所提出的运动学工作的起点是他们1995年的模型，该模型是用最近的数据进行测试的，比如作为载荷函数的轨迹方差（他们提出的一个实验）。弹性在分子运动功能中的作用，他们已经在不完美的布朗棘轮马达的背景下证明了这一点，他们在运动蛋白（通过灵活的蛋白质链接连接到它的负载）中进行了研究，也在细胞分裂期间的染色体运输中，在跨细胞膜的蛋白质易位中，以及在连接F1和Fo马达的弹性偶联中，包括ATP合酶。通过建立一个新的中尺度流体力学数学/计算框架，研究了水环境对分子马达运行的影响。这种方法结合了传统的流体连续描述和模拟布朗运动的随机力。他们使用类似的方法来模拟生物细胞内渗透驱动的水运输。为了从实验生物学家以越来越快的速度产生的大量多学科数据中找到意义，需要对生命系统进行数学建模和计算机模拟。现在我们知道，生物细胞中充满了蛋白质马达，它们就像微型机器人一样，通过化学能量消耗驱动的机械过程来进行生命活动。这些马达运作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，人们才能判断所提出的机制是否能够定量地解释观察到的任何特定分子马达的行为。该项目的目标是为这些分子机器的工作原理绘制详细的蓝图。

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.