Zwitterions - Effects on Stability

    Zwitterions such as the glycine zwitterion shown in the figure at right are intrinsically (i.e. in the gas phase) not very stable. Solvation is a major contribution to stabilizing zwitterions. For instance, the glycine zwitterion has been calculated to be unstable by ~18 kcal/mol, whereas the zwitterion solvated by water molecules is more stable than neutral glycine by ~11 kcal/mol.[3,4]
    The main effect of adding cations to a zwitterion is the same as that of solvation: stabilization of the zwitterion with respect to the neutral form. For instance, adding a sodium ion to the glycine zwitterion makes the zwitterion almost as stable as the sodiated glycine charge solvation structure. For small glycine-like systems the amount of zwitterion stabilization depends strongly on the nature of the cation.[6,7] Larger alkali ions stabilize the zwitterion less than smaller alkali ions. However, for glycine none of the alkali ions is able to bring down the energy of the zwitterion below the level of the most stable charge solvation structure. The alkali ion does not only affect the stability of the zwitterion, but also the satiability of various charge solvation structures with respect to each other. For the small alkali ions such as sodium the charge solvation structure CS1 (see figure at left) is the most stable structure, whereas CS2 is more stable for the larger alkali ions such as rubidium.[7]
    For glycine-like amino acids (points a-f in the figure below) there is a nice nearly-linear relationship between zwitterion stability (as calculated at the B3LYP/DZVP level) and proton affinity (PA).[7] However, for systems different from "glycine-like", other effects factor in causing deviation from the linearity observed for points a-f. This is evident for N-amidino-glycine, point g in the figure below. In N-amidino-glycine the amino group present in glycine is replaced by a guanidino group making it much more basic (increased PA) than glycine, but causing structural changes as well.[8] The effect most likely responsible for the deviation from the ΔE vs. PA linearity is the fact that the electrical dipole in the N-amidino-glycine zwitterion is different in orientation than in the glycine zwitterion.

FIGURE (right): Zwitterion (ZW) stability (as calculated at the B3LYP/DZVP level) with respect to charge solvation stability (CS) of sodiated systems as a function of amino acid proton affinity (PA).
(a) glycine, (b) alanine, (c) alpha-isobutyric acid
(d) sarcosine, (e) proline, (f) N,N-dimethyl-glycine
(g) N-amidino-glycine

    In fact, in sodiated glycine-like zwitterions the zwitterion dipole is almost ideally aligned with the sodium charge, making the salt bridge structure unusually stable. In N-amidino-glycine the dipole is less favorably aligned with the sodium charge as schematically shown in the figure to the left. Hence, the zwitterion is less stable than expected on the basis of a comparison with glycine-like systems and the very high PA value of N-amidino-glycine. Poorer dipole-charge alignment is also present in salt bridge structures of small peptides, an effect contributing to the generally lower stability of cationized peptide zwitterions compared to cationized amino acids. For instance, the sodiated diglycine zwitterion is 14 kcal/mol less stable than the charge solvation structure, whereas the sodiated glycine zwitterion is only 3 kcal/mol above the charge solvation structure.[5]
    For cationized peptides, self-solvation becomes with increasing peptide chain length an increasingly more important effect for stabilizing charge solvation structures. This is evident for sodiated pentaglycine, where solvation of the sodium ion is maximized with the presence of five solvating >C=O groups (figure below, right).[5] For hexaglycine, coordination of five >C=O groups (not six) is observed as well.[5] (See molecular modeling results confirmed by cross section measurements.) Hence, for peptides larger than pentapeptides, charge solvation structures cannot benefit much more by an additional increase of system size. However, complete self-solvation of a zwitterion structure with three charges (2 positive, 1 negative) is only achieved for considerably larger peptides (possibly as large as a 15-residue peptide, 5 residues per charge). Therefore, salt bridge structures are expected to benefit from increasing system size in the range from 5 to 15 residues. An example of a zwitterionic peptide in this size range is probably protonated bradykinin.[14]

Note on B3LYP/DZVP:

    Density Functional Theory (DFT) calculation using exchange and correlation functionals calculated by Becke’s Three Parameter Hybrid Method (Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652) including the LYP (Lee, Yang, Parr) expression (B3LYP) with a basis set of double-zeta quality for the valence electrons plus polarization functions on heavy atoms comparable to 6-31G* (Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J. Chem. 1992, 70, 560-571).