Oligoglycine Appendix

• Glycine: GlyH⁺, GlyNa⁺
• Diglycine: Gly₂H⁺, Gly₂Na⁺
• Protonated Oligoglycines: Gly_nH⁺, n = 3-6
• Sodiated Oligoglycines: Gly_nNa⁺, n = 3-6

Gly₁
    Structure (a) in the figure at right corresponds to the most stable conformer of GlyH⁺ obtained by DFT calculations using a B3LYP/6-311G** basis set. The dihedral angle α is 0° [see depiction in (b)], but rotation about the C-N axis does not appear to be severely hindered, since the conformation with α=60° is only 1 kcal/mol higher in energy. For GlyNa⁺ two structures are possible, one with the sodium ion bound to neutral glycine in its amino acid form [structure (c)], and one with Na⁺ bound to zwitterionic glycine [structure (d)]. A full geometry optimization on a MP2/6-311++G** level indicates, that the first form (c) is some 3.6 kcal/mol more stable than the second one (d) after zero point energy correction. The much faster DFT B3LYP/6-311++G**calculation agrees with the MP2 result within 0.3 kcal/mol. The structures found by molecular modeling are with minor deviations the same as the ab initio conformations. The single minima located for GlyH⁺ (α=60°) and GlyNa⁺ (zwitterion; α=0°) correspond to the structures shown above. For Na⁺ bound to Gly in its amino acid form three minima were found, the lowest one being that shown in structure (c) above.

Gly₂
    Molecular mechanics calculations indicate that diglycine ionized at the N-terminus, Gly₂H⁺ [structure (a) in figure at right] and Gly₂Na⁺ [structure (b)], prefer a cyclic arrangement as depicted for structure (a). The corresponding extended linear conformations are ~7 kcal/mol higher in energy. Note, that the dihedral angle ω along the peptide bond, which usually is ~180° ("trans") in any oligoglycine or other peptide systems, is ~0° ("cis") for the lowest-energy conformers in both of these dimer systems. In this arrangement the protonated N-terminus can be better solvated by the C-terminal oxygen. The sodiated glycine form (c) is determined by the solvation of Na⁺ by the two >C=O groups. The terminal -NH₂ is either also bound to Na⁺ or forms a hydrogen bond with the amide hydrogen as shown in (c), the latter structure being ~1.5 kcal/mol more stable. DFT calculations on Gly₂Na⁺ indicate at all levels of theory, that form (c) is more stable by more than 10 kcal/mol than form (b).

Gly_nH⁺, n=3-6
    Semiempirical geometry optimizations carried out on structures obtained from molecular mechanics calculations for Gly₄H⁺ and Gly₅H⁺ indicate that salt bridge structures of the form I are substantially less stable than simple charge solvation structures of type II.

Thus, for energetic reasons protonated oligoglycines of the form I can be excluded as possible candidate structures not only for the small Gly₂H⁺ and Gly₃H⁺, but also when the chain is long enough to allow separation of the two positive charges and formation of a salt bridge between the positive N-terminus and the negative C-terminus. Molecular mechanics results indicate that protonated oligoglycines prefer a cyclic arrangement where one of the N-terminal amino hydrogens forms a hydrogen bond to the C-terminal >C=O group (see figure below). Some of the amide >C=O groups are also bound to the N-terminus to help solvate the charge. The lowest-energy conformers are held together by three such H-bonds, which fold the peptide into a pretty spherical shape. More extended conformers are typically higher in energy and there is a reasonable correlation between the energy of a conformation and its calculated cross section or degree of unfolding.

Gly_nNa⁺, n=3-6
    The Gly_nNa⁺ structures (where Gly_n is a non-zwitterion) obtained by molecular mechanics are determined by the solvation of Na⁺ by >C=O. Even for the hexamer, all >C=O groups can coordinate around the Na⁺ ion, but the lowest-energy conformers (for n=4-6) have 4 to 5 such electrostatic O-Na bonds. This is still a large coordination number and combined with the rather long O-Na bonds of 2.3 to 2.5 Å, it causes the relatively small peptide to unfold and span around Na⁺ like an open umbrella, resulting in a quite oblate shape (see figure below).

    The conformers of zwitterionic oligoglycine bound to Na⁺ are all fairly compact. In all cases we were able to locate only a small number of different conformers using our simulated annealing procedure, and in all cases there exists one particularly stable conformation, shown in the figure below for Gly₅Na⁺. All of those "salt bridge" conformers have in common that both Na⁺ and -NH₃⁺ are bound to the carboxylate group via an electrostatic bond and 1 or 2 H-bonds, respectively. The amide >C=O groups coordinate either to Na⁺ or to -NH₃⁺. The coordination number for Na⁺ is typically 4 (3 for n=3), and
-NH₃⁺ forms between 2 (for n=3,4) to 3 (for n=6) hydrogen bonds.