Three 5 ns independent Molecular dynamics (MD) simulations were performed for HIV-1 Integrase (IN) wild-type (WT), G140A/G149A and T66I/S153Y mutants, respectively. Conformational change was explored after the mutations via cluster and domain cross correlation map (DCCM) analysis. The whole structure analysis shows that the dimension of the active pocket of IN maintains constant in despite of the mutation, while the T66I/S153Y and G140A/G149A mutants exhibit higher mobility in the whole system and functional loop region, respectively. The better correlation between the simulated data of the root mean square fluctuation (RMSF) of IN WT and the experimental B factor values confirms the validity of flexibility analysis. The cluster analysis shows that the functional loop region of IN possesses open-close motion after the mutation, and the systems ranked according to the open-close possibility from big to small are G140A/G149A, T66I/S153Y and WT. Finally, the DCCM analysis results show that both the attenuation of the functional region division and the decrease of the motive correlation of the DDE motif residues may cause the drug resistance for the G140A/G149A and T66I/S153Y mutants. The results generated from the above simulation should be theoretically useful for understanding the drug resistance mechanism of the IN mutant, also for the further drug design based on the structure of HIV-1 IN.

Key words: integrase, mutant, cluster analysis, domain cross correlation map, conformational change