Protein-ligand binding is largely determined by multiple noncovalent interactions (NCIs), which may exhibit synergistic or antagonistic effects. Here, we applied an approach combining PDB statistics with QM/MM calculations to quantify relationships among five major NCIs: halogen bonds (XB), hydrogen bonds (HB), cation-π interactions (CP), π-π interactions (PP), and salt bridges (SB). Statistical analysis showed that 69.28% of the ligands with SB acceptors interact with protein residues, followed by HB acceptors (65.21%) and XB donors (62.76%). Energy analysis revealed the strongest antagonism between the CP acceptor and SB acceptor (median ΔESyn = 1.31 kcal/mol) and the strongest synergy between the HB donor and acceptor (-0.73 kcal/mol). The effects are enhanced when their interaction distances are R2 = 0.980). These results reveal a complicated NCI network, which provides guidance for rational ligand design.
Luo et al. (Mon,) studied this question.