Computer-aided understanding and engineering of enzymatic selectivity.

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.