Molecular dynamics insights into binding selectivity of inhibitors toward BRD4 and CBP

Highlights: • Cross-correlation analysis reveals significant effect of inhibitor bindings on conformations of BRD4 and CBP. • MM-GBSA calculations uncover that inhibitors produce stronger bindings to CBP than BRD4. • Residue-based free energy decomposition detects hot spots of inhibitor bindings to BRD4 and CBP. Molecular dynamics (MD) simulations and binding free energy calculations were run to explore binding selectivity of inhibitors F3J, EX1, and E2T toward bromodomain-containing protein 4 (BRD4) and CREB binding protein (CBP). Dynamics analysis reveals dependence of binding selectivity on conformational changes and movement modes of BRD4 and CBP. Meanwhile, estimations of residue-based free energy decomposition not only recognize hot spots of inhibitor bindings to two proteins but also reveal that residues Trp81/Leu1109, Pro82/Pro1110, Gln85/Gln1113, Val87/Val1115, Leu92/Leu1120, Leu94/Ile1122, Asn140/Asn1168, and Ile146/Val1174 in BRD4/CBP generate obvious binding difference, which is responsible for binding selectivity of inhibitors toward BRD4 and CBP.