Theoretical investigation of kinesin-1 and other molecular motors

驱动蛋白-1和其他分子马达的理论研究

• 批准号: 7499148
• 负责人: LIAO Y CHEN
• 金额: $ 9.95万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499148
• 关键词: ATP Hydrolysis; Accounting; Cells; Chromosomes; Computer Simulation; Degenerative Disorder; Development; Dimensions; Event; Freedom; Friction; Goals; Head; In Vitro; Investigation; Kinesin; Learning; Leg; Length; Limb structure; Mechanics; Methods; Microscopic; Microtubules; Modeling; Molecular; Molecular Motors; Motion; Motor; Movement; Nature; Neck; Neurodegenerative Disorders; Neurotransmitters; One-Step dentin bonding system; Operative Surgical Procedures; Optics; Pathway interactions; Range; Rate; Reaction; Research; Sampling; Shapes; Simulate; Solutions; System; Techniques; Temperature; Theoretical Studies; Time; Training; Walking; Weight; cancer therapy; cell motility; feeding; foot; insight; man; millisecond; molecular dynamics; molecular mechanics; nanoscale; particle; prevent; programs; protein function; research study; sensor; single molecule; size; theories; three-dimensional modeling; vibration

DESCRIPTION (provided by applicant): Kinesin is recognized as the workhorse of the cell, hauling chromosomes, neurotransmitters and other vital cargo along microtubules. Understanding kinesin motility will provide new insight into how motor proteins function and possibly open new avenues of investigation for the treatment of cancer and neuro-degenerative diseases. The recent development of optical force clamp and other single-molecule techniques has led to in vitro experimental studies of a single kinesin molecule walking along a microtubule. Through experiments, a great deal has been learned about the motion of kinesin-1 powered by ATP hydrolysis. But we are still not clear about the machinery that drives the transitions between the relevant states. We can see how this little biped's limbs move, but not the operations of its actuators and sensors that produce and control the motion. The experimental results clearly point to the three dimensional (3D) nature of the motor dynamics and the importance of the shape and size of the kinesin heads. However, the current theoretical studies are generally limited to one dimension (1D) models, in which the two heads of kinesin-1 are represented by two shapeless particles moving in 1D. Their conformational and orientational changes are not properly accounted for as essential actions of walking. We propose to advance the theoretical understanding of kinesin-1 by pursuing two specific aims: 1. Study 3D three-body (3D3B) model of kinesin-1. We will model kinesin as a system of 15 degrees of freedom: Two heads as two bodies, free to rotate, six degrees of freedom each; Two neck-linkers as two springs, they join the heads to the hinge (the stalk) that is biased by the cargo load. We will develop techniques of transition-path sampling (TPS) with negative-friction Langevin dynamics (NFLD), hyper molecular dynamics (HMD), and fluctuation dynamics around minimum energy paths (FDMEP). We will employ these highly efficient methods to investigate the 3D dynamics of the 3D3B kinesin model. 2. Establish in silico experiments of kinesin motility. Molecular mechanics force fields will be fed to the PI's TPS with NFLD, HMD, and FDMEP programs to generate transition paths for the chemo-mechanical transitions of the atomistic model of kinesin-1. This enables in silico experiments of kinesin stepping events that are milliseconds apart with atomic, sub-picosecond precision.

描述（由申请人提供）：驱动蛋白被认为是细胞的主力，沿微管拖运染色体，神经递质和其他重要货物。了解运动蛋白的运动能力将为运动蛋白的功能以及可能为治疗癌症和神经差异疾病的治疗开放新的研究途径提供新的见解。光电夹和其他单分子技术的最新发展导致对沿着微管行走的单个驱动蛋白分子进行体外实验研究。通过实验，已经了解了由ATP水解驱动的驱动蛋白1的运动。但是我们仍然不清楚驱动相关状态之间过渡的机械。我们可以看到这个小双子的肢体如何移动，而不是产生和控制运动的执行器和传感器的操作。实验结果清楚地表明，运动动力学的三维（3D）性质以及驱动蛋白头的形状和大小的重要性。但是，当前的理论研究通常仅限于一个维度（1D）模型，其中驱动蛋白-1的两个头由两个在1D中移动的无形粒子表示。它们的构象和取向的变化不能正确地解释为行走的基本行动。我们建议通过追求两个具体目标来提高对运动蛋白-1的理论理解： 1。研究3D三体（3D3B）驱动蛋白1模型。我们将把运动蛋白建模为一个15度的自由度的系统：两个头部作为两个身体，可以自由旋转，每个自由度六个自由度；两个脖子链接作为两个弹簧，将头部连接到铰链（茎）上，这些铰链（茎）被货物负荷偏见。我们将开发具有负摩擦LANGEVIN动力学（NFLD），超分子动力学（HMD）和最小能量路径（FDMEP）周围的波动动力学的过渡路径采样技术（TPS）。我们将采用这些高效的方法来研究3D3B驱动蛋白模型的3D动力学。 2。在驱动蛋白运动的硅实验中建立。分子力学力场将用NFLD，HMD和FDMEP程序喂入P​​I的TPS，以生成驱动蛋白1原子模型的化学机械跃迁的过渡路径。这可以在动力蛋白垫脚事件的硅实验中，这些阶梯式事件与原子，次秒精度相距甚远。