Laccase is a copper-containing enzyme that with the help of dioxygen could catalyze the oxidation of various types of substrates,especially capable of degradation towards phenols,and is widely used in industrial chemical synthesis and waste water treatment.We report here a systematic study combining quantum mechanics and molecular dynamics to illustrate the influence of different substitutions on the binding affinity and reactivity between phenols and laccase.We picked 21 model derivatives based on the collection of reported substrates of laccase,and then performed MM-GBSA calculation after 5ns molecular dynamics simulations,which demonstrated that Asp206,Asn264 and Phe265 have significant contributions on the binding eneygy by H-bond and nonpolar interatcion.More Van der Waals contact between the substrate and the pocket of laccase should benifit the binding process.Quantum mechanical computation on the oxidative half reactions of the 21 substrates in a model laccase active site showed that deprotonation of substrate by Asp206 is critical to reduce the energy penalty,and electron-donating groups could significantly increase the reactivity while electron-withdrawing groups on the contrary.Our study provides directive information for further design of more effective mutants of laccase.