RESUMO
The conformation of models of the epoxy-derivative of the glycosaminoglycan heparin has been studied by molecular mechanics calculations using a MM2-like force field extended with parameters for the oxirane ring. Two dimers, two trimers and several higher homologs modeling heparin epoxide were investigated, assuming the preferred 5H0 ring form of 2,3-anhydro-alpha-L-guluronic acid residue. Two-dimensional (phi; psi) maps of dimers showed the location of the energetically preferred conformers. Starting from the most stable dimer conformers, structures of trimers and other oligomers were derived and optimized, with an exhaustive search of the preferred sidechain conformers. The effect of solvation on conformation was analyzed using a continuum model of solvent. The present calculations indicate a significant flexibility of the heparin epoxide chain.
Assuntos
Compostos de Epóxi/química , Heparina/análogos & derivados , Heparina/química , Configuração de Carboidratos , Modelos Moleculares , Oligossacarídeos/química , Solventes/farmacologia , TermodinâmicaRESUMO
The conformation in solution of the pentasaccharide methyl glycoside (As-G-A*-Is-AM; 1), which represents the binding site of heparin for Antithrombin III, has been investigated using molecular mechanics and 1H-n.m.r. spectroscopy. The pentasaccharide has a rather rigid (As-G-A*) and a more flexible (Is-AM) region. A simplified model of 1, comprising two conformations, corresponding to the 1C4 and the 2S0 forms of the iduronate residue, and modified at the G-A* glycosidic linkage with respect to the energy minimum, reproduces most of the observed 3J values and n.O.e. enhancements. The possible role in the binding to Antithrombin III of a low-energy conformer, not observed in solution, is discussed.
Assuntos
Antitrombina III , Heparina , Sítios de Ligação , Configuração de Carboidratos , Sequência de Carboidratos , Dissacarídeos , Glucosamina , Ácido Idurônico , Espectroscopia de Ressonância Magnética , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Oligossacarídeos , TermodinâmicaRESUMO
The 1H-n.m.r. 3J values for the L-iduronic acid (IdoA) residues for solutions in D2O of natural and synthetic oligosaccharides that represent the biologically important sequences of dermatan sulfate, heparan sulfate, and heparin have been rationalized by force-field calculations. The relative proportions of the low-energy conformers 1C4, 2S0, and 4C1 vary widely as a function of sequence and of pattern of sulfation. When IdoA or IdoA-2-sulfate units are present inside saccharide sequences, only 1C4 and 2S0 conformations contribute significantly to the equilibrium. This equilibrium is displaced towards the 2S0 form when IdoA-2-sulfate is preceded by a 3-O-sulfated amino sugar residue, and towards the 1C4 form when it is a non-reducing terminal. For terminal non-sulfated IdoA, the 4C1 form also contributes to the equilibrium. N.O.e. data confirm these conclusions. Possible biological implications of the conformational flexibility and the counter-ion induced changes in conformer populations are discussed.
Assuntos
Glicosaminoglicanos , Ácido Idurônico , Ácidos Urônicos , Configuração de Carboidratos , Sequência de Carboidratos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , SulfatosRESUMO
Ab initio computations with different basis sets (up to 6-31 + G* *) on methylsulfate and N-methylsulfate anions and on the ionic and neutral forms of acetic acid are presented. The atomic charges for the O-sulfo group, computed using the Merz-Kollman method at the highest level of theory, were inserted in a MM2-derived force-field; its current parametrization affords a 0.22 A root-mean-square deviation with respect to five crystal structures of sulfated monosaccharides.