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

Background: In the study of biomolecular structures and interactions the polar hydrogen-p bonds (Hp-p) 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-pi 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-pi donors include R2NH, RNH2, ROH, and C6H5OH; and the acceptors are aromatic amino acids, peptide bond unit, and small conjugate pi-groups. The Hp-pi 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-p 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-pi interactions are point to p-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-pi 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-p interactions are in the region from 2.30 to 3.00 angstrom at the perpendicular direction to the p-plane, much longer than the common hydrogen bonds (similar to 1.9 angstrom). (5) Like common hydrogen bond interactions, the Hp-p interactions are less affected by solvation effects.