Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Ave, Suite 3064 BST3, Pittsburgh, Pennsylvania 15260, USA.
J Chem Phys. 2013 Sep 28;139(12):121912. doi: 10.1063/1.4816375.
The Anton supercomputing technology recently developed for efficient molecular dynamics simulations permits us to examine micro- to milli-second events at full atomic resolution for proteins in explicit water and lipid bilayer. It also permits us to investigate to what extent the collective motions predicted by network models (that have found broad use in molecular biophysics) agree with those exhibited by full-atomic long simulations. The present study focuses on Anton trajectories generated for two systems: the bovine pancreatic trypsin inhibitor, and an archaeal aspartate transporter, GltPh. The former, a thoroughly studied system, helps benchmark the method of comparative analysis, and the latter provides new insights into the mechanism of function of glutamate transporters. The principal modes of motion derived from both simulations closely overlap with those predicted for each system by the anisotropic network model (ANM). Notably, the ANM modes define the collective mechanisms, or the pathways on conformational energy landscape, that underlie the passage between the crystal structure and substates visited in simulations. In particular, the lowest frequency ANM modes facilitate the conversion between the most probable substates, lending support to the view that easy access to functional substates is a robust determinant of evolutionarily selected native contact topology.
最近开发的 Anton 超级计算技术可用于高效的分子动力学模拟，使我们能够在明确的水分子和脂质双层中以全原子分辨率检查微秒至毫秒级的蛋白质事件。它还使我们能够研究网络模型（在分子生物物理学中得到广泛应用）预测的集体运动在多大程度上与全原子长时模拟所表现出的运动一致。本研究集中在为两个系统生成的 Anton 轨迹上：牛胰蛋白酶抑制剂和古细菌天冬氨酸转运蛋白 GltPh。前者是一个经过深入研究的系统，有助于为比较分析方法提供基准，后者为谷氨酸转运蛋白的功能机制提供了新的见解。这两个模拟得出的主要运动模式与各系统的各向异性网络模型 (ANM) 预测的模式非常吻合。值得注意的是，ANM 模式定义了集体机制或构象能景观上的途径，这些机制或途径是晶体结构和模拟中访问的亚稳态之间转变的基础。特别是，最低频率的 ANM 模式促进了最可能亚稳态之间的转换，支持了这样一种观点，即易于进入功能亚稳态是进化选择天然接触拓扑的稳健决定因素。
