Competition between π and Non-π Cation-Binding Sites in Aromatic Amino Acids: A Theoretical Study of Alkali Metal Cation (Li+, Na +, K+)-Phenylalanine Complexes

Abstract

To understand the cation-π interaction in aromatic amino acids and peptides, the binding of M+ (where M+ = Li+, Na+, and K+) to phenylalanine (Phe) is studied at the best level of density functional theory reported so far. The different modes of M+ binding show the same order of binding affinity (Li+ > Na+ > K+), in the approximate ratio of 2.2:1.5:1.0. The most stable binding mode is one in which the M+ is stabilized by a tridentate interaction between the cation and the carbonyl oxygen (O=C), amino nitrogen (-NH2), and aromatic π ring; the absolute Li+, Na+, and K+ affinities are estimated theoretically to be 275, 201, and 141 kJ mol-1, respectively. Factors affecting the relative stabilities of various M +-Phe binding modes and conformers have been identified, with ion-dipole interaction playing an important role. We found that the trend of π and non-π cation bonding distances (Na+-π > Na +-N > Na+-O and K+ -π > K +-N > K+-O) in our theoretical Na+/K +-Phe structures are in agreement with the reported X-ray crystal structures of model synthetic receptors (sodium and potassium bound lariat ether complexes), even though the average alkali metal cation-π distance found in the crystal structures is longer. This difference between the solid and the gas-phase structures can be reconciled by taking the higher coordination number of the cations in the lariat ether complexes into account.