Aromatic Residues\nin Proteins: Re-Evaluating the Geometry\nand Energetics of π–π, Cation−π, and\nCH−π Interactions

Aromatic residues\ncan participate in various biomolecular\ninteractions,\nsuch as π–π, cation−π, and CH−π\ninteractions, which are essential for protein structure and function.\nHere, we re-evaluate the geometry and energetics of these interactions\nusing quantum mechanical (QM) calculations, focusing on pairwise interactions\ninvolving the aromatic amino acids Phe, Tyr, and Trp and the cationic\namino acids Arg and Lys. Our findings reveal that π–π\ninteractions, while energetically favorable, are less abundant in\nstructured proteins than commonly assumed and are often overshadowed\nby previously underappreciated, yet prevalent, CH−π interactions.\nCation−π interactions, particularly those involving Arg,\nshow strong binding energies and a specific geometric preference toward\nstacked conformations, despite the global QM minimum, suggesting that\na rather perpendicular T-shape conformation should be more favorable.\nOur results support a more nuanced understanding of protein stabilization\nvia interactions involving aromatic residues. On the one hand, our\nresults challenge the traditional emphasis on π–π\ninteractions in structured proteins by showing that CH−π\nand cation−π interactions contribute significantly to\ntheir structure. On the other hand, π–π interactions\nappear to be key stabilizers in solvated regions and thus may be particularly\nimportant to the stabilization of intrinsically disordered proteins.