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

Area of Science:

• Computational Chemistry
• Structural Biology
• Biophysics

Background:

• Polar hydrogen-π (Hp-π) bonds are a significant class of molecular interactions in biomolecular structures.
• These interactions involve 11 of 20 natural amino acids in proteins and all four nucleic acids in DNA/RNA.

Purpose of the Study:

• To investigate the nature and strength of polar hydrogen-π (Hp-π) interactions in proteins.
• To compare the performance of different quantum chemical methods for studying Hp-π bonds.
• To quantify Hp-π interaction energies in various environments (vacuum and solutions).

Main Methods:

• Employed high-level quantum mechanical (QM) methods, specifically CCSD/6-311+G(d,p)+H-Bq, for calculations.
• Compared CCSD/6-311+G(d,p)+H-Bq with B3LYP, CCSD, and CCSD(T) methods using different basis sets.
• Calculated Hp-π interaction energies for amino acid pairs (Ser-Phe, Lys-Phe, His-Phe, Tyr-Phe) and various donor/acceptor groups.

Main Results:

• The B3LYP method inadequately describes Hp-π interactions, while CCSD/6-311+G(d,p)+H-Bq provides results close to the CCSD(T)/cc-pVTZ benchmark.
• Hp-π interactions are point-to-π-plane interactions with diverse conformations and a broad energy range, exceeding those of common hydrogen bonds.
• In proteins, Hp-π interaction energies range from 10 to 30 kJ/mol, comparable to or greater than typical hydrogen bonds.

Conclusions:

• The CCSD/6-311+G(d,p)+H-Bq method is suitable for studying Hp-π interactions, unlike B3LYP.
• Hp-π interactions exhibit unique characteristics, including longer bond lengths (2.30–3.00 Å) than hydrogen bonds (~1.9 Å).
• Solvation effects have a minimal impact on Hp-π interactions, similar to common hydrogen bonds.