Theoretical study on the polar hydrogen-π (Hp-π) interactions between protein side chains

BACKGROUND: In the study of biomolecular structures and interactions the polar hydrogen-π bonds (Hp-π) are an extensive molecular interaction type. In proteins 11 of 20 natural amino acids and in DNA (or RNA) all four nucleic acids are involved in this type interaction. RESULTS: The Hp-π in proteins are studied using high level QM method CCSD/6-311 + G(d,p) + H-Bq (ghost hydrogen basis functions) in vacuum and in solutions (water, acetonitrile, and cyclohexane). Three quantum chemical methods (B3LYP, CCSD, and CCSD(T)) and three basis sets (6-311 + G(d,p), TZVP, and cc-pVTZ) are compared. The Hp-π donors include R(2)NH, RNH(2), ROH, and C(6)H(5)OH; and the acceptors are aromatic amino acids, peptide bond unit, and small conjugate π-groups. The Hp-π interaction energies of four amino acid pairs (Ser-Phe, Lys-Phe, His-Phe, and Tyr-Phe) are quantitatively calculated. CONCLUSIONS: Five conclusion points are abstracted from the calculation results. (1) The common DFT method B3LYP fails in describing the Hp-π interactions. On the other hand, CCSD/6-311 + G(d,p) plus ghost atom H-Bq can yield better results, very close to the state-of-the-art method CCSD(T)/cc-pVTZ. (2) The Hp-π interactions are point to π-plane interactions, possessing much more interaction conformations and broader energy range than other interaction types, such as common hydrogen bond and electrostatic interactions. (3) In proteins the Hp-π interaction energies are in the range 10 to 30 kJ/mol, comparable or even larger than common hydrogen bond interactions. (4) The bond length of Hp-π interactions are in the region from 2.30 to 3.00 Å at the perpendicular direction to the π-plane, much longer than the common hydrogen bonds (~1.9 Å). (5) Like common hydrogen bond interactions, the Hp-π interactions are less affected by solvation effects.