Collaborative Research: Multiscale Methods for the Molecular Simulation of Sensory Mechanotransduction Channels

这项研究将创造新的数学和数值方法来研究在C.线虫，一种拥有最简单的触觉神经系统的蠕虫。主要的问题是弥合相关的生物时间尺度之间的差距，在这种情况下，打开和关闭的离子通道，和直接分子动力学模拟的时间尺度，这是短得多。在这个方向上的一个步骤将是创建一个新的时间和空间自适应方案（AVI和HiGrid），加速在给定温度下可访问的不同蛋白质构象的采样。此外，技术（弦方法和ABF算法），以探索系统的稳定构象之间的过渡途径将被开发。这种方法的新奇在于，路径是根据许多集体变量来计算的，而不是通常所做的原子的笛卡尔坐标。这导致了更大的鲁棒性和物理上更相关的通路。感知触摸的能力取决于位于感觉神经元膜上的纳米尺寸的离子通道。当在皮肤上施加力时，这些通道打开，让离子流入或流出细胞，这种现象称为门控。这些纳米机器是一个复杂装置的一部分，该装置将机械力转化为电信号，并将信息从皮肤传输到神经元。通过汇集生物学，高性能计算和数学方面的专业知识，研究人员将在迄今为止已知的唯一后生动物机械转导通道中产生门控机制的原子精确模型。

This research will create new mathematical and numerical methods to study the dynamics of large proteins found in touch sensory neurons of C. elegans, a worm with one of the simplest touch sensory nervous system. The main issues are bridging the gap between relevant biological time scales, in this case the opening and closing of ion channels, and time scales accessible to direct molecular dynamics simulations which are much shorter. A step in this direction will be the creation of a new time and space adaptive scheme (AVI and HiGrid) which accelerates the sampling of the different protein conformations accessible at a given temperature. In addition, techniques (the string method and the ABF algorithm) to explore transition pathways between stable conformations of the system will be developed. The novelty of this approach is that the pathways are computed in terms of many collective variables instead of the Cartesian coordinates of the atoms as is usually done. This leads to greater robustness and physically more relevant pathways.The ability to sense touch depends on nanometer sized ion channels located in the membrane of sensory neurons. When force is exerted in the skin these channels open to let a flow of ions go in or out of the cell, a phenomenon called gating. These nano-machines are part of a complex apparatus which converts mechanical force into electric signals and transports information from the skin to neurons. By bringing together expertise in biology, high performance computing and mathematics, the investigators will produce atomically accurate models of the gating mechanism in the only metazoan mechanotransduction channel known to date.