title: Molecular modeling of the interaction between heparan sulfate and cellular growth factors: bringing pieces together.
abstract: Heparan sulfate is a polysaccharide belonging to the glycaminoglycan family. It interacts with numerous proteins of the extracellular matrix, in particular cellular growth factors. The number of experimental protein-heparin sulfate complexes obtained by crystallography or nuclear magnetic resonance is limited. Alternatively, computational approaches can be employed. Generally, they restrain the conformation of the glycosidic rings and linkages in order to reduce the complexity of the problem. Modeling the interaction between protein and heparan sulfate is indeed challenging because of the large size of the fragment needed for a strong binding, the flexibility brought by the glycosidic rings and linkages and the high density of negative charges. We propose a two-step method based on molecular docking and molecular dynamics simulation. Molecular docking allows exploring the positioning of a rigid heparin sulfate fragment on the protein surface. Molecular dynamics refine selected docking models by explicitly representing solvent molecules and not restraining the polysaccharide backbone. The interaction of a hexamer of heparin sulfate was studied in interaction with fibroblast growth factor 2 and stromal cell-derived factor 1α. This approach shed light on the plasticity of the growth factors interacting with heparan sulfate. This approach can be extended to the study of other protein/glycosaminoglycan complexes.
authors.affiliation: Centre de Recherches sur les Macromolécules Végétales-CNRS, 601 rue de la Chimie, BP 53, 38041 Grenoble Cedex 9, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sapay
authors.forename: Eric
authors.initials: E
authors.lastname: Cabannes
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
authors.forename: Anne
authors.initials: A
authors.lastname: Imberty
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D054377:Chemokine CXCL12; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate