Exploring protein-berberine interactions via molecular dynamics and MM/ GBSA calculations

Structural modification on berberine has garnered considerable attention among medicinal chemists as a means to enhance its therapeutic potential. The dissection of macrobiomolecule-berberine interactions is pivotal for guiding such modifications. In this study, four diverse crystal complexes of protein-berberine were selected, and simulated by molecular dynamics, in which each complex was conducted five times. Subsequently, the interactions of protein-berberine were collected, and analyzed by in-house scripts. Our findings indicated that the four oxygen atoms, namely O15, O16, O17, and O18, actively participated in the formation of hydrogen bonds and water bridges; the carbon atoms within the D and E rings were able to form hydrophobic interactions more than other carbon atoms; the positively charged N7 atom predominantly participated in the formation of cation-pi interactions; pi-pi interactions were prevalent in the A, B, and D rings, with their frequency influenced by the presence of the residues Trp, Tyr, His, and Phe in the binding pocket. In the free energy decomposition analysis, the terms Delta G_Lipo and Delta G_vdW emerged as the most significant contributors to the overall energy, with Delta G_vdW accounting for over 50% of the energy contribution. Notably, the contribution of Delta G_Packing to the free energy was substantially greater than that of Delta G_Hbond, which contributed less than 1%. These insights into molecular interactions provide valuable guidance for the structural modification of berberine, such as site selection of structural modification, group optimization with the improvement of van der Waals and hydrophobic interactions, and the trade-off between hydrogen bonding and pi-packing interactions in terms of interaction weights.