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

The low affinity of nonpolar groups for water gave birth to one of the significant supramolecular forces known as hydrophobic interaction as early as 1937. While the precise origins of this phenomenon remain debated, the significant role of London dispersion forces in stabilizing nonpolar complexes is well-established. This article presents a comprehensive investigation of the nature and strength of CH3•••H3C (methyl-methyl) interactions within the amino acid residues of proteins, employing a combination of quantum mechanical calculations and custom Python code. Analysis of isolated mimetic dipeptide models reveals that these interactions are weak, with interaction energies ranging from -2.40 to -6.94 kJ/mol. These energies are primarily attributed to dispersion forces, supplemented by a minor electrostatic contribution. Even though CH3•••H3C interactions are weak, the cumulative effect of such interactions is vital for the flexible enzymatic center and drug-protein interactions. Although experimental characterization of these weak interactions is challenging, our computational studies, presented herein, suggest that solution-phase 13C NMR and the recently developed gas-phase terahertz (THz) spectroscopy offer promising avenues for obtaining spectroscopic signatures of CH3•••H3C interactions and elucidating their strength and molecular origin.