The sodium ion affinities of simple di-, tri-, and tetrapeptides

The sodium ion affinities (binding energies) of nineteen peptides containing 2-4 residues have been determined by experimental and computational approaches. Na+-bound heterodimers with amino acid and peptide ligands (Pep(1), Pep(2)) were produced by electrospray ionization. The dissociations of these Pep(1)-Na+-Pep(2) ions to Pep(1)-Na+ and Pep(2)-Na+ were examined by collisionally activated dissociation to construct a ladder of relative affinities via the kinetic method. The accuracy of this ladder was subsequently ascertained by experiments using several excitation energies for four peptide pairs. The relative scale was converted to absolute affinities by anchoring the relative values to the known Na+ affinity of GlyGly, The Na+ affinities of AlaAla, HisGly, GlyHis, GlyGlyGly, AlaAlaAla, GlyGlyGlyGly, and AlaAlaAlaAla were also calculated at the MP2(full)/6-311 + G(2d,2p) level of ab initio theory using geometries that were optimized at the MP2(full)/6-31G(d) level for AlaAla or HF/6-31G(d) level for the other peptides; the resulting values agree well with experimental Na+ affinities. Increasing the peptide size is found to dramatically augment the Na+ binding energy. The calculations show that in nearly all cases, all available carbonyl oxygens are sodium binding sites in the most stable structures. Whenever side chains are available, as in HisGly and GlyHis, specific additional binding sites are provided to the cation. Oligoglycines and oligoalanines have similar binding modes for the di- and tripeptides, but differ significantly for the tetrapeptides: while the lowest energy structure of GlyGlyGlyGly-Na+ has the peptide folded around the ion with all four carbonyl oxygens in close contact with Na+, that of AlaAlaAlaAla-Na+ involves a pseudo-cyclic peptide in which the C and N termini interact via hydrogen bonding, while Na+ sits on top of the oxygens, of three nearly parallel C=O bonds.