Population distribution of flexible molecules from maximum entropy analysisusing different priors as background information: application to the phi,psi-conformational space of the a-(1→2)-linked mannose disaccharide presentin N- and O-linked glycoproteins
2010 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 16, 3684-3695 p.Article in journal (Refereed) Published
The conformational space available to the flexible molecule a-D-Manp-(1→2)-a-D-Manp-OMe, amodel for the a-(1→2)-linked mannose disaccharide in N- or O-linked glycoproteins, is determinedusing experimental data and molecular simulation combined with a maximum entropy approach thatleads to a converged population distribution utilizing different input information. A database survey ofthe Protein Data Bank where structures having the constituent disaccharide were retrieved resulted inan ensemble with >200 structures. Subsequent filtering removed erroneous structures and gave thedatabase (DB) ensemble having three classes of mannose-containing compounds, viz., N- and O-linkedstructures, and ligands to proteins. A molecular dynamics (MD) simulation of the disaccharide revealeda two-state equilibrium with a major and a minor conformational state, i.e., the MD ensemble. Thesetwo different conformation ensembles of the disaccharide were compared to measured experimentalspectroscopic data for the molecule in water solution. However, neither of the two populations werecompatible with experimental data from optical rotation, NMR 1H,1H cross-relaxation rates as well ashomo- and heteronuclear 3J couplings. The conformational distributions were subsequently used asbackground information to generate priors that were used in a maximum entropy analysis. Theresulting posteriors, i.e., the population distributions after the application of the maximum entropyanalysis, still showed notable deviations that were not anticipated based on the prior information.Therefore, reparameterization of homo- and heteronuclear Karplus relationships for the glycosidictorsion angles f and y were carried out in which the importance of electronegative substituents on thecoupling pathway was deemed essential resulting in four derived equations, two 3JCOCC and two 3JCOCHbeing different for the f and y torsions, respectively. These Karplus relationships are denotedJCX/SU09. Reapplication of the maximum entropy analysis gave excellent agreement between theMD- and DB-posteriors. The information entropies show that the current reparametrization of theKarplus relationships constitutes a significant improvement. The fH torsion angle of the disaccharide isgoverned by the exo-anomeric effect and for the dominating conformation fH = -40◦ and yH = 33◦.The minor conformational state has a negative yH torsion angle; the relative populations of the majorand the minor states are ~3 : 1. It is anticipated that application of the methodology will be useful toflexible molecules ranging from small organic molecules to large biomolecules.
Place, publisher, year, edition, pages
2010. Vol. 8, no 16, 3684-3695 p.
Maximum entropy, Karplus relation, disaccharides
Research subject Organic Chemistry
IdentifiersURN: urn:nbn:se:su:diva-42005DOI: 10.1039/c003958fISI: 000280527500015OAI: oai:DiVA.org:su-42005DiVA: diva2:343486