Spontaneous formation of hydrophobic domains in isolated peptides

Aromatic amino acids are known for their hydrophobicity and the active role they play in protein folding. Here, we investigate the intrinsic propensity of small peptides to form hydrophobic domains in the absence of solvent water molecules. The structures of three aromatic-rich isolated peptides, Ac-Phe-Phe-NH2 (FF), Ac-Trp-Tyr-NH2 (WY), and Ac-Phe-Phe-Phe-NH2 (FFF), all in the gas phase, have been studied by infrared-ultraviolet (IR/UV) double resonance laser spectroscopy, aided by dispersion-corrected density functional theory (DFT-D) calculations. Spontaneous formation of hydrophobic domains is systematically observed, whatever the secondary structure adopted by the backbone. Various types of aromatic-aromatic arrangements have been identified and associated to specific secondary structures, illustrating the interplay between the hydrophobic clusters and the backbone. Backbone NH amide groups surrounded by aromatic rings have also been evidenced and are found to contribute significantly to the stabilization of aromatic pairs. These results suggest that the formation of aromatic clusters involving contiguous residues might be a very efficient process leading to the formation of hydrophobic domains in the early stages of protein folding, well before a hydrophobic collapse into the tertiary structure.