Strength and Character of R-X…π Interactions Involving Aromatic Amino Acid Sidechains in Protein-Ligand Complexes Derived from Crystal Structures in the Protein Data Bank

Funding Source

National Science Foundation, National Institutes of Health

Grant Number

HRD-1505219, 1R15GM113193-01,5R25GM060926-10,5RL5GM118966-03


Department of Chemistry

Document Type


Publication Date



Here, we investigate the strengths of R-X…π interactions, involving both chlorine and bromine, in model systems derived from protein-ligand complexes found in the PDB. We find that the strengths of these interactions can vary significantly, with binding energies ranging from −2.01 to −3.60 kcal/mol. Symmetry adapted perturbation theory (SAPT) analysis shows that, as would be expected, dispersion plays the largest role in stabilizing these R-X…π interactions, generally accounting for about 50% to 80% of attraction. R-Br…π interactions are, for the most part, found to be stronger than R-Cl…π interactions, although the relative geometries of the interacting pair and the halogen’s chemical environment can also have a strong impact. The two factors that have the strongest impact on the strength of these R-X…π interactions is the distance between the halogen and the phenyl plane as well as the size of the halogen σ-hole.


DOI: 10.3390/cryst7090273

Funding text

Acknowledgments: The authors gratefully acknowledge support from the NSF HBCU-UP program (HRD-1505219), the NIH R15 program (1R15GM113193-01), the NIH RISE program (5R25GM060926-10), and the NSF BUILD program (5RL5GM118966-03).