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-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[double bond]C), amino nitrogen (--NH(2)), and aromatic pi 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-pi 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.

Quantification and rationalization of the higher affinity of sodium over potassium to protein surfaces

“…The ion specificity at the backbone is primarily attributable to interactions with the carbonyl oxygen of the amide group, whereas the selectivity at other side-chain groups also can have some contribution from cation-aromatic ring interactions in phenylalanine. The latter interactions were shown to be stronger for Na ϩ than for K ϩ as well (16); however, they cannot be described accurately within standard force fields. The very different nature and amino acid content of the proteins under study is reflected in varying total numbers of ions at the protein surface and relative contributions from different protein parts.…”

Substituent Effects on Non‐Covalent Interactions with Aromatic Rings: Insights from Computational Chemistry

“…Global minimum complex of Na + with phenylanalnine reported by Tsang and coworkers. [77] Scheme 6. Selection of substituted arenes studied in the context of anion/p interactions.…”

“…Tsang and coworkers [77] studied the interaction of alkali cations with phenylalanine, demonstrating that the cation/p interaction is competitive with other non-covalent interactions in the gas phase (see Figure 12). The preferred binding mode was found to be a triScheme 4.…”

Alkali Metal Complexes of the Dipeptides PheAla and AlaPhe: IRMPD Spectroscopy

“…[8,13,22,23] . Experimentally, sodium and/or potassium ion complexes of both Ala [12] and Phe [16] have been characterized by IRMPD spectroscopy, and we can also note examples of structural studies using this technique with other amino acid complexes.…”