Adaptive QM/MM Methods for Proton Transfer in Complex Environments

科罗拉多大学丹佛分校的Hai Lin得到了化学理论、模型和计算方法项目的支持，该项目开发和应用计算方法来研究生物环境中的质子转移。就像我们每天走过房屋、办公室、学校和商店的大门一样；每一分钟，生命所必需的离子都会穿过生物细胞的大门。细胞表面的这些门被称为离子通道和转运体。这些特殊的蛋白质位于细胞膜中，控制着哪些离子以及何时穿过细胞膜。在这些蛋白质中有CLC质子/氯逆向转运蛋白，它以耦合的方式调节质子的流入和氯离子的流出。关于CLC质子/氯反转运体如何在转移质子方面发挥作用的细节仍然难以捉摸。此外，质子是否(以及如何)在通过易位孔的过程中与氯离子相互作用仍在争论中。林教授和他的研究团队，包括两名本科生，通过计算机模拟寻找这些问题的答案。他们正在开发结合了量子力学和经典力学模型的先进计算技术。然后，他们应用这些方法来研究CLC转运蛋白。由于故障的门可能会阻碍我们到达目的地，故障的离子通道和转运体可能会扰乱正常的生命过程并导致疾病。LIN小组的研究试图加深我们对CLC转运体如何在基础分子水平上工作的理解，这反过来可能有助于开发与这些蛋白质功能障碍相关的疾病的新疗法。质子转移的格洛特斯穿梭机制涉及共价键和氢键的动态重组。而反应力场(也称为分子力学或MM)和多态经验价键模型在处理水解离和质子跳跃方面是有效的。这些模型在复杂环境中的扩展是具有挑战性的，因为需要快速增加的潜在参数来解释更多的价组态。此外，对于理想的量子力学(QM)描述的键断裂/形成过程，缺少电子结构信息。由于计算成本较高，QM模拟仅限于小模型系统(~数百个原子)。LIN小组正在开发新的自适应分配QM/MM方法，用于复杂环境中的质子转移。自适应分区方案的特点是一个运行中的平滑更新的移动QM区域，它跟随质子到任何地方。因此，有限大小的QM区域变得无限大，原则上，只要需要，就可以支持模拟。新算法被应用于大肠杆菌CLC逆向转运蛋白原型的研究。利用动态计算的QM/MM势和对质子的显式处理，动力学模拟探索了CLC反向转运体中疏水孔道的水化、水线的形成、质子的转移和氯离子的质子化。

Hai Lin of the University of Colorado at Denver is supported by an award from the Chemical Theory, Models and Computational Methods program to develop and apply computational methods to study proton transfer in biological environments. Just as every day we walk through doors of houses, offices, schools, and shops; every minute, ions that are essential to life pass through doors of biological cells. These doors on the surface of cells are called ion channels and transporters. Situated in cellular membranes, these special proteins control which ions move across the membrane and when. Among these proteins are the CLC proton/chloride antiporters, which regulate the influx of protons and the outflow of chloride ions in a coupled manner. Details of how the CLC proton/Chloride antiporters work in transferring protons remain elusive. Moreover, it is still under debate if (and how) the proton interacts with chloride ions during its journey through the translocation pore. Professor Lin and his research team, which includes two undergraduate students, seek answers to these questions through computer simulations. They are developing advanced computational techniques that combine quantum- and classical-mechanical models. They then apply these methods to study the CLC transporters. As malfunctioning doors can block us from reaching our destination, malfunctioning ion channels and transporters can disrupt normal life processes and cause diseases. The research by the Lin group seeks to deepen our understanding of how the CLC transporters work at a fundamental, molecular level, which may, in turn, assist the development of novel therapies for diseases related to these protein malfunctions.The Grotthuss-shuttling mechanism for proton transfer involves dynamical reorganizations of covalent and hydrogen bonds. While reactive force fields (also called molecular-mechanics, or MM) and multistate empirical valence bond models are efficient in treating water dissociation and proton hopping. The extension of these models in complex environments is challenging because of the rapidly increasing number of potential parameters needed to account for more valence configurations. Moreover, electronic-structure information is missing for the bond breaking/forming processes, which are described ideally by quantum mechanics (QM). QM simulations are limited to small model systems (~hundreds of atoms) due to high computational costs. The Lin group is developing novel adaptive-partitioning QM/MM methods for proton transfer in complex environments. The adaptive-partitioning schemes feature an on-the-fly smoothly updated mobile QM region that follows the proton wherever it goes. As such, a finite-size QM region becomes infinite and can, in principle, sustain simulations as long as needed. The new algorithms are applied to the study of a prototype CLC antiporter from E. coli. With on-the-fly computed QM/MM potentials and an explicit treatment of protons, the dynamics simulations explore the hydrophobic pore hydration, water wire formation, proton translocation, and chloride ion protonation in the CLC antiporter.