Revealing binding selectivity of inhibitors toward bromodomain-containing proteins 2 and 4 using multiple short molecular dynamics simulations and free energy analyses

摘要: Emerging evidences indicate bromodomain-containing proteins 2 and 4 (BRD2 BRD4) play critical roles in cancers, inflammations, cardiovascular diseases other pathologies. Multiple short molecular dynamics (MSMD) simulations combined with mechanics generalized Born surface area (MM-GBSA) method were applied to investigate the binding selectivity of three inhibitors 87D, 88M 89G towards BRD2 over BRD4. The root-mean-square fluctuation (RMSF) analysis indicates that structural flexibility BRD4 is stronger than BRD2. Moreover calculated distances between Cα atoms centres ZA_loop BC_loop are also bigger rank free energies using MM-GBSA agrees well determined by experimental data. results show 87D can bind more favourably BRD4, while has better on Residue-based free-energy decomposition was utilized estimate inhibitor-residue interaction spectrum not only identify hot spots but demonstrate several common residues, including (W370, W374), (P371, P375), (V376, V380) (L381, L385) belonging (BRD2, BRD4), generate significant difference