How does a small peptide choose how to bind a metal ion? IRMPD and computational survey of CS versus Iminol binding preferences

Binding to proteins and peptides in condensed phases, it is normal for alkali and alkaline earth metal ions to interact preferentially with Lewis-basic oxygen, nitrogen and similar open chelation points, while late transition metals like cobalt, nickel and copper characteristically deprotonate and bind to amide nitrogens along the peptide chain. Parallel to these contrasting condensed-phase binding-mode alternatives, metal ions in the gas phase can form complexes with small peptides in several complexation modes, among them the charge-solvated (CS) and the Iminol patterns. Reported here is a computational study of the factors determining the choice between these patterns in the gas phase for model ligands, dialanine and trialanine, also including illustrative experimental spectroscopic results for Ag+(Ala)(3) using the infrared multiple photon dissociation (IRMPD) technique (which has also provided previous experimental results for many of the ions studied here). Across a survey of 29 metal ions in normal oxidation states (+1, +2 and +3), unexpectedly strong correlations are found (for each charge state) between the preference for CS versus Iminol binding and the overall binding energies of the ions. Ions of +1 charge invariably prefer CS binding, while those with higher charge exhibit variable preferences. Within a given charge state, Iminol binding is more favorable, and overall binding is stronger, for light metal ions and for metal ions ("transition metals") late in the periodic table. The tendency to go from CS to Iminol in the gas phase is generally parallel to the tendency to bind deprotonated amide nitrogens in condensed-phase, but with possible divergence between the differing environments at the point where the tendencies cross over near Mg(II). Hard/soft character of the metal ions correlates to some extent with the binding preferences, but this correlation shows numerous discrepancies. For "main-group" metal ions, electrostatic character of the binding is suggested by excellent scaling of binding energies with a scaling parameter q/R, while a contribution of enhanced binding in addition to the electrostatic binding energy is indicated for "transition" metals