Crystal structures of the isomeric dipeptides l-glycyl-l-methionine and l-methionyl-l-glycine

The zwitterionic, isomeric, title compounds, Gly-Met and Met-Gly are methionine-containing dipeptides, which show very different conformations in the solid state.


Chemical context
Methionine and methionyl peptides play an important role in protein oxidation.The sulfur atom in methionine can easily be oxidized by free radicals or oxidants and lead to sulfur radical cations (Bobrowski & Holcman, 1989) or a corresponding sulfoxide (Scho ¨neich, 2005).The formation of reactive radical cations is responsible for methionyl protein damage and misconformation, which has been implicated in numerous inflammatory (Vogt, 1995) and age-related diseases (Scho ¨neich, 2005;Stadtman et al., 2005).
Gly-Met (Gly = glycine, Met = methionine) and its reverse sequence, Met-Gly, are two simple dipeptides.It has been shown that the position of methionine with respect to the N-terminus of the peptide determines the mechanism of oxidation of methionyl peptides.For instance, in photosensitized oxidation reactions, substantial amounts of radical cations stabilized with sulfur-nitrogen (S;N) three-electron bonded species were observed with Met-Gly, while similar stabilization of the radical cations was not observed with Gly-Met (Pedzinski et al., 2009).In collision-induced radical dissociation, Gly-Met leads to the loss of a CH 3 -S-CH CH 2 fragment from the peptide, while such dissociation in Met-Gly leads to the loss of a CH 3 S • (Lau et al., 2013) radical.Thus, the difference in methionine position leads to quite different reaction intermediates, which may eventually affect the stability of the peptide and its biological function.
The oxidation of methionine peptides is determined by several factors, including peptide structure, the position of methionine within the sequence, neighboring groups to methionine, nature of the oxidants, and solvent properties.The conformation of the peptide is also an important factor that needs to be considered to understand the mechanism of oxidation.Peptides can exist in either cationic, zwitterionic, or anionic conformations, depending on the solvent and the pH.The present report describes the zwitterionic structures of Gly-Met and Met-Gly dipeptides.We believe that some of the differences observed in the literature related to methionyl peptide oxidations could be attributed to the conformation of the peptide in solution.

Structural commentary
Both of the dipeptides are in their zwitterionic forms in the solid state (Fig. 1).The amide N1 atom of both Gly-Met and Met-Gly is in the protonated NH 3 + form, and the C6/O2/O3 carboxylic groups are in their deprotonated (COO) À forms, as evidenced by the C-O distances of 1.2598 (13) and 1.2546 (13) A ˚in Gly-Met and 1.2534 (9) and 1.2635 (8) A ˚in Met-Gly.The C-NH 3 distance is 1.4809 ( 14) A ˚in Gly-Met and 1.4855 (8) in Met-Gly.The backbone of the Gly-Met molecule is extended, with its six torsion angle magnitudes in the range 163.44 (9)-177.94(8) � .Thus, the ten atoms of the chain are close to coplanar with a mean deviation of 0.091 A ˚.The backbone of the Met-Gly molecule is substantially kinked at C3.The eight-atom segment containing the carboxylate group is planar to within a mean deviation of 0.056 A ˚, and the five-atom segment containing the S atom is planar to within a mean deviation of 0.086 A ˚.These two planes intersect at C3, forming a dihedral angle of 70.502 (13) � .The absolute configurations of both molecules were confirmed from their refined Flack parameters (Parsons et al., 2013), with values of 0.02 (2) for Gly-Met and 0.011 (11) for Met-Gly.

Supramolecular features
Intermolecular interactions in both structures are dominated by N-H� � �O hydrogen bonds, some of which are bifurcated.In Gly-Met (Table 1), the NH 3 + group donates hydrogen bonds to three separate molecules, and the N-H group donates to a fourth (Fig. 2), forming a complex three-dimensional array of hydrogen bonds.Graph sets (Etter et al., 1990) include C 1 1 (5) and C 1 1 (8) chains and R 4 4 (22) loops.In Met-Gly (Table 2), the NH 3 + group also donates hydrogen bonds to three different molecules (Fig. 3), but the N-H group does not participate in intermolecular interactions and makes a very non-linear [N-H� � �O = 110.6 (10) � ] intramolecular contact to an O atom of the carboxylate group.Nevertheless, the hydrogen-bonding array is three-dimensional, and graph sets include C 1 1 (8) chains, C 2 2 (6) chains and R 4 4 (22) loops.

Figure 1
The molecular structures of Gly-Met and Met-Gly showing 50% displacement ellipsoids.
slowly in small increments with agitation and keeping the test tube at 333 K in a water bath.The solutions were allowed to cool and left undisturbed at room temperature over two weeks for slow evaporation and crystallization to yield colorless plates of Gly-Met and large colorless needles of Met-Gly.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.All H atoms were located in difference maps and those on carbon were treated as riding in geometrically idealized positions with C-H distances = 1.00A ˚for R 3 CH, 0.99 A ˚for CH 2 and 0.98 A ˚for methyl.
U iso (H) values were assigned as 1.2U eq for the attached C atom (1.5U eq for methyl).The positions of the H atoms attached to N atoms were refined.Their U iso values were assigned as 1.2U eq for the NH groups and 1.5U eq for NH 3 .

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes. Fractional

Figure 3
Figure 3Hydrogen bonding in Met-Gly.H atoms on C are not shown.

Figure 2
Figure 2Hydrogen bonding in Gly-Met.H atoms on C are not shown.

Table 3
Experimental details.