Enzymes offering chemo-, regio-, and stereoselectivity enable the asymmetric synthesis of high-value chiral molecules. Unfortunately, the drawback that naturally occurring enzymes are often inefficient or have undesired selectivity toward non-native substrates hinders the broadening of biocatalytic applications. To match the demands of specific selectivity in asymmetric synthesis, biochemists have implemented various computer-aided strategies in understanding and engineering enzymatic selectivity, diversifying the available repository of artificial enzymes. Here, given that the entire asymmetric catalytic cycle, involving precise interactions within the active pocket and substrate transport in the enzyme channel, could affect the enzymatic efficiency and selectivity, we presented a comprehensive overview of the computer-aided workflow for enzymatic selectivity. This review includes a mechanistic understanding of enzymatic selectivity based on quantum mechanical calculations, rational design of enzymatic selectivity guided by enzyme-substrate interactions, and enzymatic selectivity regulation via enzyme channel engineering. Finally, we discussed the computational paradigm for designing enzyme selectivity in silico to facilitate the advancement of asymmetric biosynthesis.

提供化学选择性、区域选择性和立体选择性的酶能够实现高价值手性分子的不对称合成。不幸的是，天然存在的酶通常效率低下或对非天然底物具有不良选择性的缺点阻碍了生物催化应用的拓宽。为了满足不对称合成中特定选择性的需求，生物化学家已经实施了各种计算机辅助策略来理解和工程化酶的选择性，从而使可用的人工酶库多样化。在这里，鉴于整个不对称催化循环，包括活性口袋内的精确相互作用和酶通道中的底物转运，可能会影响酶的效率和选择性，我们全面概述了酶促选择性的计算机辅助工作流程。本综述包括基于量子力学计算对酶选择性的机械理解、酶-底物相互作用指导的酶选择性的合理设计以及通过酶通道工程进行的酶选择性调控。最后，我们讨论了设计酶选择性的计算范式in silico以促进不对称生物合成的进步。