Typical Aromatic Noncovalent Interactions in Proteins: A Theoretical Study Using Phenylalanine

A systematic study of CH center dot center dot center dot pi, OH center dot center dot center dot pi, NH center dot center dot center dot pi and cation center dot center dot pi interactions has been done using complexes of phenylalanine in its cationic. anionic. neutral, and zwitterionic forms with CH4, H2O, NH3, and NH4+ 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 (rho(r)) and the values of rho(r) showed linear relationship to the binding energies (E-total). The estimated Etotal from supermolecule, fragmentation, and p(r) approaches suggest that cation center dot center dot center dot pi interactions are in the range of 36 to 46 kcal/mol, whereas OH center dot center dot center dot pi, and NH center dot center dot center dot pi interactions have comparable strengths of 6 to 27 kcal/mol and CH center dot center dot center dot pi 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 rho(r) at bcps which suggests that OH center dot center dot center dot pi and NH center dot center dot center dot pi interactions show positive, whereas CH center dot center dot center dot pi and cation center dot center dot center dot pi 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. (C) 2008 Wiley Periodicals, Inc. J Comput Chem 30: 1392-1404, 2009