Theoretical investigation of kinesin-1 and other molecular motors

描述（由申请人提供）：肌动蛋白被认为是细胞的主力，沿着微管运输染色体，神经递质和其他重要货物。了解运动蛋白的运动性将为运动蛋白的功能提供新的见解，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已经导致了单个驱动蛋白分子沿着微管行走的体外实验研究。通过实验，我们对ATP水解驱动的激酶-1的运动有了大量的了解。但我们仍然不清楚驱动相关状态之间转换的机制。我们可以看到这个小两足动物的四肢是如何运动的，但不能看到它的执行器和传感器是如何产生和控制运动的。实验结果清楚地指出了运动动力学的三维（3D）性质以及运动头的形状和大小的重要性。然而，目前的理论研究一般局限于一维（1D）模型，其中kinesin-1的两个头部由两个在一维中运动的无形状粒子表示。它们的构象和取向变化并没有被恰当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kinesin-1的理论理解：

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.