随着科技的飞速发展，云计算、大数据与人工智能时代的到来，理论计算模拟在化学、生物、材料等领域发挥着越来越重要的作用。近年来，量子力学/分子力学（QM/MM）方法与加强采样方法（如umbrella sampling、metadynamics等）相结合的模拟方法正在逐渐被应用于复杂有机和生物体系的研究中。多年来，我们一直从事多尺度的模拟方法发展与应用的理论研究。在本项目中，我们将结合多层QM/MM方法与自由能模拟方法，提高模拟实体系统的大小和复杂性，并将应用此方法研究几个重要的生物酶与仿生催化环化反应和环加成反应，对比研究酶催化反应过程和机理，考察不同的反应活性和手性选择性，探讨底物与酶的柔性构象以及熵效应，深入理解生物酶催化的特异性或专一性以及仿生系统的重要催化功能等。本研究将为理性设计、开发与优化新型仿生酶等人工合成催化剂提供一定的理论基础和指导。

With the development of science and technology as well as the arrival of the era of the cloud computing, big data and artificial intelligence, computational and theoretical simulations are playing more and more important roles in many research fields such as chemistry, biology, material science, and so on. Recently, quantum mechanics/molecular mechanics (QM/MM) methods combined with enhanced sampling methods (such as umbrella sampling, metadynamics, etc.) have been developed and applied to study complex organic and biological systems. For the last few years, we have focused on the development and application of multi-scale simulations. In this project, we combine multi-layer QM/MM methods with free energy simulation methods to improve the size and complexity of real systems in the simulations. Then, we will apply this multi-layer QM/MM free energy method to study several important enzymes and biomimetic systems catalyzed cyclization and cycloaddition reactions. We will investigate the enzyme-catalyzed reaction processes and mechanisms, examine different catalytic activities and enantioselectivities, discuss the flexible conformations of the substrate and the enzyme as well as entropic effect, and understand deeply the specificity of enzymatic catalysis and the important catalytic functions of biomimetic systems. Insights gained from this study will provide a theoretical guidance for rational design, development and optimization of novel artificial catalysts, such as biomimetic enzymes.