Adaptive QM/MM Methods for Proton Transfer in Complex Environments

位于丹佛的科罗拉多大学的林海获得了化学理论、模型和计算方法项目的一项奖励，以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、学校和商店的门一样，每分钟，生命所必需的离子都穿过生物细胞的门。细胞表面的这些门被称为离子通道和转运蛋白。位于细胞膜中，这些特殊的蛋白质控制哪些离子穿过膜以及何时穿过膜。这些蛋白质中包括CLC质子/氯反向转运蛋白，它以耦合方式调节质子的流入和氯离子的流出。CLC质子/氯反向转运蛋白如何转移质子的细节仍然难以捉摸。 此外，质子在通过易位孔的过程中是否（以及如何）与氯离子相互作用仍有争议。林教授和他的研究团队，其中包括两名本科生，通过计算机模拟寻求这些问题的答案。他们正在开发先进的计算技术，结合联合收割机量子和经典力学模型。 然后他们应用这些方法来研究CLC转运蛋白。由于故障的门可以阻止我们到达我们的目的地，故障的离子通道和运输工具可以扰乱正常的生命过程并导致疾病。Lin团队的研究旨在加深我们对CLC转运蛋白如何在基本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Grotthuss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是有效的处理水的离解和质子跳跃。 这些模型在复杂环境中的扩展是具有挑战性的，因为需要考虑更多的价态配置的潜在参数的数量迅速增加。此外，电子结构信息丢失的键断裂/形成过程，这是理想的量子力学（QM）描述。由于计算成本高，QM模拟仅限于小模型系统（约数百个原子）。Lin小组正在开发用于复杂环境中质子转移的新型自适应分区QM/MM方法。自适应分区方案的特点是在飞行中平滑更新的移动的QM区域，无论质子走到哪里，它都会跟随质子。因此，有限大小的QM区域变成无限的，并且原则上可以根据需要维持模拟。将新算法应用于大肠杆菌CLC反向转运蛋白的研究。杆菌在飞行计算的QM/MM电位和显式处理的质子，动力学模拟探讨疏水孔水合，水线形成，质子易位，和氯离子质子化的CLC反向转运。

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.