钙离子模型的发展及其在生物体系计算中的应用

在生物体系中，钙离子通过与生物分子的相互作用，直接或间接地在肌肉收缩，神经信号传递，细胞信号调节和命运决定等多个关键问题中起到至关重要的作用。近几年来，多个可以转运钙离子的通道结构得到了解析，使得相关生物体系的分子动力学模拟研究变得尤为迫切。然而，目前在经典的不可极化力场中，已有的钙离子模型和参数无法很好的描述钙离子和蛋白质的相互作用。因此，本项目计划发展一个新的多点钙离子模型，使之不仅可以再现钙离子在水溶液中的诸多物理化学性质，而且可以定量地描述钙离子和蛋白质分子的相互作用能，从而使得一系列与钙离子相关的生物分子体系可以在经典力场的框架下进行定量的分子动力学模拟研究。作为验证，我们将把该离子模型应用到钙调蛋白的模拟中并与已知实验结果进行比对。进一步地，我们将利用该离子模型研究TRPV1离子通道的通透性，选择性以及热敏感门控机理，从而尝试解释我们是如何感知到热的。

Calcium ions are essential in biological systems, which play crucial roles in muscle contraction, signal transduction in nervous system, cell signaling regulation and cell fate determination, etc. In the last few years, a couple of novel structures of calcium-permeable ion channels have been determined, which make the computational studies on the calcium-related biosystems even more desirable. However, the existing calcium ion models in the classic non-polarizable force fields are very inaccurate in calculating the interaction energies between calcium ions and protein molecules, which hindered the relevant computational studies. Therefore, we propose to develop a new multi-site calcium model, which can not only represent the physical and chemical properties of calcium ions in solution, but also quantitatively calculate the interaction energies between calcium ions and proteins. This will allow many important calcium-related biomolecules to be studied quantitatively with classic molecular dynamics simulations. As a validation, we will apply the new calcium ion model to the calmodulin system, and compare the simulation results to the experimental ones. Furthermore, we will use this new calcium ion model to study the ion permeability, selectivity and gating mechanisms of the thermosensitive TRPV1 channel, in the hope of partially answering the question about how we feel heat.