Computer Simulations of Enzymes

使用分子动力学(MD)和组合量子的计算机模拟 力学/分子力学(QM/MM)方法能够描述结构和动力学 指由酶催化的蛋白质和化学反应。一个准确的和 计算上有效的能量函数是必要的。然而，挑战依然存在： QM方法的精度，QM子系统的电子密度与QM方法的兼容性 MM子系统的经典力场，以及从头算QM/MM方法大写的成本 关于相关质量管理方法的准确性和可靠性。为了应对这些挑战，我们 开发了一系列从头算QM/MM方法，用于反应路径优化和自由 能量计算、QM/MM最小自由能路径和QM/MM神经网络 网络(QM/MM-NN)方法。这项建议旨在进一步发展从头开始的QM/MM方法 及其在重要酶氧化还原过程研究中的应用 结合神经网络表示的从头算力场。 我们的长期目标是开发和建立准确的第一原理和密度 基于泛函理论(DFT)的MD和QM/MM模拟作为实验的平等伙伴 研究酶和蛋白质，并提供对化学和氧化还原过程的洞察 生物系统。我们的目标如下：(1)我们的目标是以更多的成本制造从头开始的QM/MM模型 更准确的QM/MM能量，用于QM描述以及静电和VDW相互作用 在QM和MM子系统之间。(2)我们的目标是开发一种组合计算 模型探索还原电位变异性的关键分子决定因素 金属蛋白。我们将提供对化学和氧化还原反应机理的详细见解 生物系统，特别是漆酶。(3)我们的目标是发展精准 水和蛋白质的力场，用于生物应用的模拟，超越了 传统的力场形式及其在精度上的局限性。 拟议的发展将利用量子理论的发展。 电子理论，如线性响应理论和精确的多电子方法 非共价相互作用，并利用生物数据科学中的机器学习方法 系统模拟。拟议的工作将导致从头开始QM/MM的重大进展 方法和力场，以及对蛋白质结构-功能范式的洞察 以及酶中重要的氧化还原过程和反应机理。此外，它还将导致 新药和酶抑制剂设计的方法学发展。

Computer simulations using molecular dynamics (MD) and the combined quantum mechanical/molecular mechanical (QM/MM) approach are capable of describing structures and dynamics of proteins and chemical reactions catalyzed by enzymes. An accurate and computationally efficient energy function is necessary. However, challenges remain: the accuracy of QM method, the compatibility between the electron density of the QM subsystem and classical force fields for the MM subsystem, and the cost of ab initio QM/MM methods capitalizing on the accuracy and reliability of the associated QM approaches. To address these challenges, we have developed a series of ab initio QM/MM approaches on reaction path optimizations and free energy calculations, the QM/MM minimum free-energy path (QM/MM-MFEP) and the QM/MM neural network (QM/MM-NN) methods. This proposal aims to develop further the ab initio QM/MM methodology and its applications to the studies of redox processes in important enzymes, and the construction of ab initio force fields combined with neural network representations. Our long-term goals are to develop and establish accurate first-principles based and density functional theory (DFT) based MD and QM/MM simulation as an equal partner with experiments for the study of enzymes and proteins and to provide insight into chemical and redox processes in biological systems. Our aims are as follows: (1) We aim to make ab initio QM/MM models for much more accurate QM/MM energies, for the QM description and for the electrostatic and vdW interactions between the QM and MM subsystems. (2) We aim to develop a combined computational model to explore the key molecular determinants of the reduction potential variability in metalloproteins. We will provide detailed insight into chemical and redox reaction mechanisms in biological systems, in particular laccases. (3) We aim at the development of accurate force fields of water, and proteins for simulations in biological applications, going beyond the traditional force field forms and limitation in accuracy. The proposed developments will capitalize on the theoretical developments in quantum electronic theory, such as the linear response theory and accurate many-electron approach for non-covalent interactions, and leverage machine-learning methods in data science for biological system simulations. The proposed work will lead to the major advancement of the ab initio QM/MM method and force fields, and insights into the structure-function paradigm for proteins and important redox process and reaction mechanisms in enzymes. In addition, it will also lead to methodology development for design of new drugs and enzyme inhibitors.