Methyl•••Methyl Interactions in Proteins: Insights from Structural and Computational Studies.

Area of Science:

• Supramolecular Chemistry
• Biophysics
• Computational Chemistry

Background:

• Hydrophobic interactions, arising from the low affinity of nonpolar groups for water, are significant supramolecular forces.
• London dispersion forces are well-established contributors to the stabilization of nonpolar complexes.
• The precise origins of hydrophobic phenomena continue to be a subject of scientific debate.

Purpose of the Study:

• To comprehensively investigate the nature and strength of methyl-methyl (CH3•••H3C) interactions within protein amino acid residues.
• To elucidate the contributions of different forces to these interactions.
• To explore potential experimental methods for characterizing these weak interactions.

Main Methods:

• Utilized quantum mechanical calculations to analyze isolated mimetic dipeptide models.
• Developed and employed custom Python code for data analysis.
• Considered spectroscopic techniques like solution-phase 13C NMR and gas-phase terahertz (THz) spectroscopy.

Main Results:

• Methyl-methyl interactions were found to be weak, with interaction energies ranging from -2.40 to -6.94 kJ/mol.
• These interactions are primarily driven by dispersion forces, with a minor electrostatic contribution.
• The cumulative effect of these weak interactions is vital for protein structure and function.

Conclusions:

• Despite their individual weakness, CH3•••H3C interactions play a vital role in the flexibility of enzymatic centers and drug-protein interactions.
• Experimental characterization of these weak interactions is challenging but feasible.
• Solution-phase 13C NMR and gas-phase THz spectroscopy show promise for detecting and quantifying CH3•••H3C interactions.