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线虫触摸感觉神经元中发现的大型蛋白质的动力学。线虫是一种具有最简单的触摸感觉神经系统之一的蠕虫。主要问题是弥合相关生物时间尺度和直接分子动力学模拟可获得的时间尺度之间的差距，在这种情况下，离子通道的打开和关闭时间尺度要短得多。朝着这一方向迈出的一步将是创建一种新的时间和空间自适应方案(AVI和HiGrid)，该方案加快了对在给定温度下可获得的不同蛋白质构象的采样。此外，还将开发探索系统稳定构象之间转换路径的技术(弦法和ABF算法)。这种方法的新奇之处在于，路径是根据许多集体变量来计算的，而不是像通常所做的那样，计算原子的笛卡尔坐标。这导致了更强的健壮性和物理上更相关的通路。感觉触摸的能力依赖于感觉神经元膜上的纳米尺寸离子通道。当在皮肤中施加力时，这些通道打开，让离子流入或流出细胞，这一现象称为门控。这些纳米机器是一个复杂设备的一部分，该设备将机械力转换为电信号，并将信息从皮肤传输到神经元。通过结合生物学、高性能计算和数学方面的专业知识，研究人员将在迄今已知的唯一后生动物机械转导通道中产生原子上准确的门控机制模型。

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.