Insights into Protein–Ligand Noncovalent Interaction Networks: A Database Survey and Quantum Chemistry Calculation Study
Abstract
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 E 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
Fields of Study & Subjects
Crystallography and molecular interactions
Computational Drug Discovery Methods
Protein Structure and Dynamics
Publication details
- Journal / source
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Volume
- 69
- Issue
- 6
- Pages
- 6965–6975
- Publication date
- 16 February 2026
- Language
- EN