Studies on non-covalent metal cation-molecule complexes

Abstract

Noncovalent interactions between alkali metal cations (M+ = Li+, Na+ and K+) and peptides / proteins are well known to be playing vital roles in many biological regulation and recognition processes. Despite its importance, there is a lack of quantitative information on M+-ligand interactions. In this study, quantum chemical modeling calculations were carried out to determine the binding geometries and affinities, as well as the nature of bindings between M+ and biologically model compounds, i.e. alcohol, amides and amino acids. The theoretical binding affinities were further validated by mass spectrometric kinetic method measurements. In the first phase of our study, state-of-the-art high level ab initio theoretical calculations at the G2(MP2), G2(MP2,SVP) and G3 levels were carried out to determine the binding affinities of M+-alcohol and M+-amide complexes. In fact, we are the first work to report a good agreement on theoretical and experimental M+-alcohol affinities. The effect of core size and basis set superposition error (BSSE) on the calculated binding affinities were investigated in details. Using computational cost and good agreement between calculated and experimental values as the criteria, the G2(MP2,SVP)-FC (default frozen core size and without BSSE correction) and G2(MP2,SVP)-ASC (smaller core size and without BSSE corrections) levels are chosen as the benchmark level/protocol for calculating Li+/Na+ and K+ binding affinities of organic ligands. The interactions between M+ and alcohol/amide are mainly electrostatic in nature, and the increasing trend of binding affinities for larger alcohols or methyl-substituted amides is due to the alkyl/methyl substituent polarizability effect. In the second phase of our study, density functional theory (DFT) calculations at the B3-LYP/6-311+G(3df,2p)//B3-LYP/6-31G(d) level, named the B3(G2) protocol in this study, were carried out to determine the binding geometries and energies of M+-L complexes, where M+= Li+, Na+, and K+, and L= 13 building block ligands containing the functional groups of amino acids. The computationally less demanding B3-LYP calculations were found to yield reliable optimized geometries and binding energies in close agreement with those obtained by the G2(MP2,SVP)-FC and G2(MP2,SVP)-ASC level for Li+/Na+ and K+ bound complexes, respectively. The average deviation between ab initio G2 and DFT calculated binding affinities are 6.6 kJ mol-1 for the 13 M+-L complexes investigated. Our results suggest that the DFT calculations are sufficiently reliable, and it might be suitably applied to determine the binding geometries and energies of larger M+-L complexes, namely the M+-amino acid complexes. The B3(G2) binding geometries and energies for M+-glycine(Gly), M+-alanine(Ala), M+-proline(Pro), M+-serine(Ser), M+-cystein(Cys) and M+-phenylalanine(Phe) complexes were found, and the various stabilizing and destabilizing interactions/factors affecting the binding energy of M+-amino acid complexes are examined in detail. For M+-Gly and M+-Ala, the most stable complex is in the charge-solvated bidentate form, with Li+/Na+ binding to the carbonyl oxygen (C=O) and the amino nitrogen (-NH2), and K+ binding to the carboxylic oxygens. For M+-Ser, M+-Cys and M+-Phe, the most stable complex is in the charge-solvated tridentate form, with M+ binding to the carbonyl oxygen (C=O) and the amino nitrogen (-NH2), and the 'additional' -OH / -SH / phenyl-π binding site in the side chain of the amino acid. The presence of cation-π interaction in the M+-Phe complex leads to enhanced stability of the charge-solvated form relative to the zwitterionic form. The most stable form of M+-Pro is found to be in the zwitterionic form, the stability of which is driven by the greater basicity of the secondary amino group in the cyclic imino amino acid. Aside from the most stable complex, the binding geometries and energies of 'low-lying', less stable M+-amino acid complexes were found. Our results show that the major factors affecting the relative stabilities of different charge-solvated and zwitterionic M+-amino acid complexes are ion-dipole, ion-induced dipole, cation-π interactions, intramolecular hydrogen bonding, and deformation energy of the ligand upon complexation to the metal cation.