Influence of Mg2+ on the binding modes of HIV-1 integrase with thiazolothiazepine inhibitor studied by molecular simulation

We studied the Influence of Mg2+ ions on binding modes of HIV-1 integrase (IN) with thiazolothiazepine (THI) inhibitor by molecular simulation. The results in this work show that the binding process of THI and IN can be divided into two phases, the docking phase and the molecular dynamics (MD) phase. Docking results show that Mg2+ ions, the cofactors of HIV-1 IN in vivo, can remarkably affect THI binding on IN. In each chain of HIV-1 IN, two Mg2+ ions take part in the docking phase. Each of the two chains of HIV-1 IN dimer contains two Mg2+ ions. The Mg2+ ion, which binds with ASP64 and ASP116, can result in lower docking energy but higher binding specificity. Another Mg2+ ion, which binds with ASP64 and GLU152, is harmful for the THI binding on IN. The synergetic actions of these two Mg2+ ions can extend the docking energy range and strengthen the binding affinity. MD simulation results illuminate, in the best docking mode, the IN dimer having two Mg2+ ions in each core domain binds with THI conformation of cluster 1. However, this mode has to endure big structure changes so as to reach the stable state. In the MD phase, ASP116, ASN117 and PRO142 of IN show strong interactions with THI. In IN dimer, only these two Mg2+ ions binding with ASP64 and ASP116 interact with THI. O8, N9, C10, and S11 of THI are important to the binding.