Theoretical investigation of kinesin-1 and other molecular motors

描述（由申请人提供）：驱动蛋白被认为是细胞的主力，沿着微管运送染色体、神经递质和其他重要货物。了解驱动蛋白的运动性将提供新的见解，如何运动蛋白的功能，并可能开辟新的途径，调查治疗癌症和神经退行性疾病。近年来，光学力钳技术和其他单分子技术的发展使得单个驱动蛋白分子在体外实验中可以沿着微管行走。通过实验，我们对驱动蛋白-1在ATP水解作用下的运动有了大量的了解。但我们仍然不清楚驱动相关国家之间过渡的机制。我们可以看到这个小机器人的四肢是如何运动的，但不能看到产生和控制运动的执行器和传感器的操作。实验结果清楚地指出了运动动力学的三维（3D）性质以及驱动蛋白头部形状和大小的重要性。然而，目前的理论研究通常局限于一维模型，其中驱动蛋白-1的两个头部由两个在一维运动的无形状颗粒表示。他们的构象和取向的变化是不正确的占步行的基本行动。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.研究驱动蛋白1的三维三体（3D 3B）模型。我们将驱动蛋白建模为15个自由度的系统：两个头部作为两个身体，自由旋转，每个六个自由度;两个颈部连杆作为两个弹簧，它们将头部连接到由货物负载偏置的铰链（柄）。我们将开发过渡路径采样（TPS）与负摩擦朗之万动力学（NFLD），超分子动力学（HMD）和最小能量路径周围的波动动力学（FDMEP）的技术。我们将采用这些高效的方法来研究3D 3B驱动蛋白模型的3D动力学。 2.建立驱动蛋白运动性的计算机实验。分子力学力场将通过NFLD、HMD和FDMEP程序被馈送到PI的TPS，以生成驱动蛋白-1的原子模型的化学机械转变的转变路径。这使得能够以原子、亚皮秒精度进行驱动蛋白步进事件的计算机实验。

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.