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Computational studies on the interaction of ABO-active saccharides with the norovirus VA387 capsid protein can explain experimental binding data

Journal article
Authors Chaitanya A. K. Koppisetty
Waqas Nasir
F. Strino
Gustaf E Rydell
Göran Larson
Per-Georg Nyholm
Published in Journal of Computer-Aided Molecular Design
Volume 24
Issue 5
Pages 423-431
ISSN 0920-654X
Publication year 2010
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 423-431
Language en
Links dx.doi.org/10.1007/s10822-010-9353-...
Keywords Norovirus, Blood group determinants, ABO-saccharides, Molecular, docking, Molecular dynamics, blood group antigens, norwalk virus-infection, nonsense mutation, structural basis, gii-4 norovirus, secretor fut2, resistance, recognition, phenotype
Subject categories Structural Biology, Industrial Biotechnology, Clinical chemistry, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Abstract

Norovirus strains are known to cause recurring epidemics of winter vomiting disease. The crystal structure of the capsid protein of VA387, a representative of the clinically important GII.4 genocluster, was recently solved in complex with histo-blood group A- and B-trisaccharides. However, the VA387 strain is known to bind also to other natural carbohydrates for which detailed structural information of the complexes is not available. In this study we have computationally explored the fit of the VA387 with a set of naturally occurring carbohydrate ligands containing a terminal alpha 1,2-linked fucose. MD simulations both with explicit and implicit solvent models indicate that type 1 and 3 extensions of the ABO-determinant including ALe(b) and BLe(b) pentasaccharides can be well accommodated in the site. Scoring with Glide XP indicates that the downstream extensions of the ABO-determinants give an increase in binding strength, although the alpha 1,2-linked fucose is the single strongest interacting residue. An error was discovered in the geometry of the GalNAc-Gal moiety of the published crystal structure of the A-trisaccharide/VA387 complex. The present modeling of the complexes with histo-blood group A-active structures shows some contacts which provide insight into mutational data, explaining the involvement of I389 and Q331. Our results can be applicable in structure-based design of adhesion inhibitors of noroviruses.

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