Binding Selectivity of Inhibitors toward Bromodomains BAZ2A and BAZ2B Uncovered by Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations.

Two Bromodomain-Containing proteins BAZ2A and BAZ2B are responsible for remodeling chromatin and regulating noncoding RNAs. As for our current studies, integration of multiple short molecular dynamics simulations (MSMDSs) with molecular mechanics generalized Born surface area (MM-GBSA) method is adopted for insights into binding selectivity of three small molecules D8Q, D9T and UO1 to BAZ2A against BAZ2B. The calculations of MM-GBSA unveil that selectivity of inhibitors toward BAZ2A and BAZ2B highly depends on the enthalpy changes and the details uncover that D8Q has better selectivity toward BAZ2A than BAZ2B, D9T more favorably bind to BAZ2B than BAZ2A, and UO1 does not show obvious selectivity toward these two proteins. The analysis of interaction network between residues and inhibitors indicates that seven residues are mainly responsible for the selectivity of D8Q, six residues for D9T and four residues provide significant contributions to associations of UO1 with two proteins. Moreover the analysis of interaction network not only reveals warm spots of inhibitor bindings to BAZ2A and BAZ2B but also unveils that common residue pairs, including (W1816, W1887), (P1817, P1888), (F1818, F1889), (V1822, V1893), (N1823, N1894),(L1826, L1897), (V1827, V1898), (F1872, F1943), (N1873, N1944) and (V1879, I1950) belonging to (BAZ2A, BAZ2B), induce mainly binding differences of inhibitors to BAZ2A and BAZ2B. Hence, insights from our current studies offer useful dynamics information relating with conformational alterations and structure-affinity relationship at atomistic levels for novel therapeutic strategies toward BAZ2A and BAZ2B.