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NMR and molecular dynamics study of muroctasin—Implications for the bioactive conformation
Author(s) -
Pristovšek Primož,
Kidrič Jurka
Publication year - 1997
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/(sici)1097-0282(199711)42:6<659::aid-bip5>3.0.co;2-t
Subject(s) - chemistry , moiety , intramolecular force , dipeptide , stereochemistry , molecule , amide , nuclear overhauser effect , nuclear magnetic resonance spectroscopy , conformational isomerism , crystallography , peptide bond , proton nmr , molecular dynamics , nmr spectra database , two dimensional nuclear magnetic resonance spectroscopy , computational chemistry , amino acid , spectral line , organic chemistry , biochemistry , physics , astronomy
Muroctasin (N 2 ‐[(N‐acetylmuramoyl)‐ L ‐alanyl‐ D ‐isoglutaminyl]‐ N 6 ‐stearoyl‐ L ‐lysine), a potent muramyl dipeptide (MDP) analogue with increased lipophilicity, has been studied in DMSO‐d 6 solution with nmr methods and molecular dynamics (MD) simulations. The proton spectra show the presence of the α‐ and β‐anomers of the pyranosyl ring in the ratio of 3:1. The molecule is in the negative nuclear Overhauser effect (NOE) regime at 25°C and 300 MHz, but shows some positive cross peaks in the stearoyl‐lysine moiety in the NOE spectroscopy (NOESY) spectra; at 600 MHz only the stearoyl moiety remains in the positive regime. The temperature dependence of the alanyl amide proton chemical shift (−2.7 ppb/K) points to its involvement in intramolecular H bonding. An extensive conformational search in vacuo indicates that the preferred conformations contain the β‐turn like structure characterized by the intramolecular H‐bond N‐Acetyl‐CO‐HN‐Ala; it coexists with the type II β‐turn characterized by the H‐bond Mur‐CO‐H E N T ‐iGln only in some high energy structures obtained by the conformational search (relative energy > 20 kcal/mol). Such an S‐shaped conformation was never found in the 0.5 ns simulation involving explicit DMSO solvent molecules where only the Ala amide proton is significantly protected from the solvent; some (short‐lived) γ‐turns in the alanyl‐isoglutaminyl backbone are also observed. No conformational preferences of the stearoyl‐lysine moiety could be deduced from the NOE data; the increased flexibility of this part of the molecule relative to the muramoyl moiety is in agreement with the shorter local correlation times evident from NOESY spectra. The set of conformations that are most similar to the set of candidates for the bioactive conformation of MDP obtained by the CCLUES procedure [P. Pristovsěk et al. (1995), J. Chem. Inf. Comput. Sci. Vol. 35, pp. 633–639] contains no low‐energy structures, but some local conformational features found in solution are preserved. © 1997 John Wiley & Sons, Inc. Biopoly 42: 659–671, 1997