Insights into Protein–Ligand Noncovalent Interaction Networks: A Database Survey and Quantum Chemistry Calculation Study

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 Δ<i>E</i>_Syn = 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 <7.5 Å. For three-NCI systems, overall energies were well approximated by the sum of the two-NCI systems (<i>R</i>² = 0.980). These results reveal a complicated NCI network, which provides guidance for rational ligand design.