Theoretical insight into molecular mechanisms of inhibitor bindings to bromodomain-containing protein 4 using molecular dynamics simulations and calculations of binding free energies

Abstract

Molecular dynamics (MD) simulations and principal component (PC) analysis are hired to decipher binding modes of inhibitors to BRD4(1). The results display that inhibitor associations exert significant impact on the dynamics of the BC_loop and the L1_loop in BRD4(1). Binding affinities estimated by using MM-GBSA method suggest that van der Waals interactions are main factors responsible for inhibitor associations. The results from residue-based free energy decomposition find that residues Gln85, Val87, Leu92, Leu94, Cys136, Ile146, Trp81, Pro82, Phe83 and Tyr139 generate the CH-π and π-π interactions with inhibitors. Notably, Asn140 forms hydrogen bonding interactions with the current inhibitors.