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: 7883288
• 负责人: LIAO Y CHEN
• 金额: $ 10.84万
• 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/7883288
• 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; Optics; Pathway interactions; 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; operation; particle; prevent; programs; protein function; research study; sensor; single molecule; 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，沿着微管牵引染色体、神经递质和其他重要货物。了解驱动蛋白运动将为了解运动蛋白如何发挥作用提供新的见解，并可能为癌症和神经退行性疾病的治疗开辟新的研究途径。光学力钳和其他单分子技术的最新发展引发了对沿微管行走的单个驱动蛋白分子的体外实验研究。通过实验，我们对 ATP 水解驱动的驱动蛋白-1 的运动有了很多了解。但我们仍然不清楚驱动相关状态之间转变的机制。我们可以看到这个小两足动物的四肢如何移动，但看不到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了运动动力学的三维 (3D) 性质以及驱动蛋白头的形状和尺寸的重要性。然而，目前的理论研究普遍局限于一维（1D）模型，其中kinesin-1的两个头由两个在一维中运动的无形粒子表示。它们的构象和方向的变化没有被正确地解释为行走的基本动作。我们建议通过追求两个具体目标来推进对驱动蛋白-1 的理论理解： 1. 研究kinesin-1的3D三体（3D3B）模型。我们将把驱动蛋白建模为一个具有 15 个自由度的系统：两个头作为两个身体，可以自由旋转，每个有 6 个自由度；两个颈部连接器作为两个弹簧，将头部连接到因货物负载而偏置的铰链（杆）。我们将开发具有负摩擦朗之万动力学 (NFLD)、超分子动力学 (HMD) 和围绕最小能量路径的涨落动力学 (FDMEP) 的过渡路径采样 (TPS) 技术。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. 建立驱动蛋白运动的计算机实验。分子力学力场将通过 NFLD、HMD 和 FDMEP 程序输入 PI 的 TPS，以生成驱动蛋白-1 原子模型的化学机械转变的转变路径。这使得在计算机模拟实验中能够以毫秒为间隔，以原子、亚皮秒的精度进行驱动蛋白步进事件。