Typical aromatic noncovalent interactions in proteins: A theoretical study using phenylalanine

A systematic study of CH ··· π, OH ··· π, NH ··· π, and cation ··· π interactions has been done using complexes of phenylalanine in its cationic, anionic, neutral, and zwitterionic forms with CH₄, H₂O, NH₃, and NH at B3LYP, MP2, MPWB1K, and M06‐2X levels of theory. All noncovalent interactions are identified by the presence of bond critical points (bcps) of electron density (ρ( r )) and the values of ρ( r ) showed linear relationship to the binding energies (E_total). The estimated E_total from supermolecule, fragmentation, and ρ( r ) approaches suggest that cation ··· π interactions are in the range of 36 to 46 kcal/mol, whereas OH ··· π, and NH ··· π interactions have comparable strengths of 6 to 27 kcal/mol and CH ··· π interactions are the weakest (0.62–2.55 kcal/mol). Among different forms of phenylalanine, cationic form generally showed the highest noncovalent interactions at all levels of theory. Cooperativity of multiple interactions is analyzed on the basis of ρ( r ) at bcps which suggests that OH ··· π and NH ··· π interactions show positive, whereas CH ··· π and cation ··· π interactions exhibit negative cooperativity with respect to the side chain hydrogen bond interactions. In general, side chain interactions are strengthened as a result of aromatic interaction. Solvation has no significant effect on the overall geometry of the complex though slight weakening of noncovalent interactions by 1–2 kcal/mol is observed. An assessment of the four levels of theory studied herein suggests that both MPWB1K and M06‐2X give better performance for noncovalent interactions. The results also support the fact that B3LYP is inadequate for the study of weak interactions. © 2008 Wiley Periodicals, Inc. J Comput Chem 2009