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

To understand the cation-pi 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 it 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 pi and non-pi cation bonding distances (Na+-pi>Na+-N>Na+-O and K+ -pi>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-a distance found in the crystal structures is longer. Ibis 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.