Conformational studies on the bacterial cell wall peptide analog phenylacetyl‐D‐alanyl‐D‐alanine: Comparison between conformations of cell wall peptide analog and those of penicillin G

Abstract

-lnstitut des Bundesgesundhei tsam tes, and I m t it u t fur Kris tal lographie der FreienUni versitat, Berlin, Federal Republic of Germany SynopsisThe conformation of phenylacetyl-Dalanyl-Dalanine in the crystalline state was characterized by Fourier-transform ir and Raman spectroscopy and was unambiguously solved by x-ray single-crystal determination. In the crystalline state, the molecule adopts a partially folded conformation quite similar to that of another cell wall peptide, acetylDalanyl-Dalanine [Benedetti et al. (1981) J. Bid. Chem. 256, 9229-92341, although the crystal structure is stabilized by a quite different intermolecular hydrogen-bond pattern. No significant deviation from the usual truns-planar peptide group geometry was detected. The conformations accessible in the noncrystalline state were investigated by ir measurements in solution and conformational energy calculations. The theoretical study revealed that the peptide is a highly flexible molecule, since 55 minima were detected, within 3 kcal/mol, including the conformation found in the single crystal. The ir data for phenylacetyl-Dalanyl-D-alanine in different solvents were in accordance with virtually extended conformations, with some indication for weak, intramolecularly hydrogen-bonded C5-rings. These conformational data obtained for the cell wall peptide analog are compared with those known for penicillin G in the crystalline state.

Comparison between the Molecular and Crystal Structures of a Benzylpenicillin Ester and its Corresponding Sulfoxide with Drastically Reduced Biological Activity

“…This interpretation is supported by the well known fact that the side chain of penicillin G possesses a high conformational flexibility (cf. [16]) and, as proposed by theoretical calculations [17], active /Mactam antibiotics should be able to assume a conformation in solution with a -torsional angle of 160-180°, which, according to model calculations would be possible in both compounds, penamecillin as well as its sulfoxide (unpublished results).…”

“….1075 (2) .7721 (5) .4879(3) O 16 .0362 (1) .8371 (3) .3679(2) C17 -.0672 (2) .7904 (4) .3436 (3) O 18 -.0980 (2) .6953 (5) .4137(3) C19 -.1348 (3) .8745 (9) .2205(5) N20…”

Conformation–activity relationships and the mechanism of action of penicillin

“…On the other hand, the oxygen-exo orientations seen in the crystal structures of penicillin G and penicillin V also appear to be general (26). Since the -CO-NHorientation found in X-ray structures has been assumed in all previous structureactivity studies and comparisons of penicillin with N-acyl-DAla-D-Ala (26,27), it is not surprising that the orientation of the amide N-H or, indeed, of the side chain itself, have received only limited attention (28).…”

Conformational behavior of the polysaccharide backbone of murein

“…All atomic parameters used for GlcNAc were the same as in Leps et al39 For MurNAc, the atoms of the side group at C(3) were replaced by the appropriate atoms of the crystal structure of N-acetyl-D-muramic acid.40 The positions of some hydrogen atoms were idealized: The atoms H(100-102) were placed in ideal tetrahedral geometry with a C-H distance of 109 pm, H (11) was positioned at an angle C(11)0(111)H(11) of 109" and a 0-H distance of 100 pm. A set of charges was prepared using the CND0/2 approach41 for 2-deoxy-2-2\r-acetyl~no-3-O-(D-l-carboxyethyl-)-~-~-xylose.…”