Theoretical studies on potassium cation-ligand interaction

Abstract

Potassium cation is one of the most abundant metal ions in biological systems, where it is involved in numerous biochemical functions, such as stabilization of protein structures and osmotic equilibrium of cells. For a better understanding of such interactions, information about the intrinsic binding modes and energies of K+ to simple model systems ligands is essential. The present study addresses this subject by determining the geometries and energetics of K+ binding to: (a) small organic ligands, (b) aliphatic amino acids, (c) linear dipeptides (glycylglycine, GG, and alanylalanine, AA), (d) dipeptides containing phenylalanine and (e) the basic amino acid, histidine, by quantum chemical molecular modeling methods. The theoretical studies were carried out by high-level density functional theory calculations at the B3-LYP/6-311 +G(3df,2p)//B3-LYP/6-31G(d)) level of theory (abbreviated as the 'EP(K+) protocol'). Our study shows that theoretical protocol yields absolute affinities for 65 model organic ligands in excellent agreement with experimental affinities (mean absolute deviation of 4.5 kJ mol-1), in support of the reliability of the B3-LYP protocol adopted in our study. Using this EP(K+) protocol, ten stable isomers of K+ -glycine on the potential energy surface have been located and the most stable mode of K+ binding involves a bidentate interaction between the cation and the O=C and -OH sites in the charge-solvated (CS) form. We also found that the stabilization energies of these complexes can be well approximated by a linear function of the 'dipole interaction parameter (DIP)' and 'polarizability interaction parameter (PIP)'. For the larger aliphatic amino acids, we found that the most stable modes of K+ binding is still the same as K+ -glycine, even though the zwitterionic (ZW) form is stabilized more than the CS mode. The effect of alkyl chain length of the relative K+ affinities of aliphatic amino acids are also discussed. The most stable K+-GG/AA/FG/GF complexes are found to be in the charge-solvated (CS) form, with K+ bound to the two carbonyl oxygen atoms of the peptide backbone. For the FG/GF dipeptides, K+ additionally bound to the phenyl π-ring of phenylalanine are comparably stable. The K+ is found to be in close alignment with the molecular dipole moment vector of the bound ligand, indicating that electrostatic ion-dipole interaction is the key stabilizing factor in these complexes. Furthermore, the strong ion-dipole. interaction between K+ and the amide carbonyl oxygen of the peptide bond is important in determining the relative stabilities of different CS binding modes. When compared to amino acids, the most stable ZW complex is found to be much less stable than the CS form for dipeptides. The usefulness of proton affinity as a criterion for estimating the relative stability of ZW versus CS binding modes is examined. Based on the results of this study, the interaction of K+ with longer peptides consisting of aliphatic amino acids is also rationalized. Theoretical studies on protonated and potassiated histidine ([His + H/K]+) and their mass spectrometric fragmentations in the gas phase have been conducted. Fragmentation of [His + H]+ occurs when the proton attaching to Nπ is transferred to the hydroxyl oxygen (yielding [CO + H2O] or H2O), or when the backbone amino nitrogen is protonated (yielding [CO2 + NH3]). The critical energy required for the formation of [CO + H2O] is found to be much lower than that for [CO2 + NH3], in agreement with the dominant loss of [CO + H2O] observed in the low-energy (eV, laboratory scale) collision-induced dissociation (CID) mass spectrum. However, the fragmentation pattern of potassiated histidine is entirely different. While the dominant fragment in [His + H]+ corresponds to the loss of [CO + H2O], such fragment is absent in the [His + K]+ CID mass spectrum. Instead, loss of K+ is dominant in potassiated histidine, with minor fragment ions arising from the losses of CO2 and NH3 separately. The difference in fragmentation behavior between protonated and potassiated histidine are discussed.