Molecular Simulations of Carbohydrates with a Fucose-Binding Burkholderia ambifaria Lectin Suggest Modulation by Surface Residues Outside the Fucose-Binding Pocket.

Tamir Dingjan,Serge Pérez,Elizabeth Yuriev,Anne Imberty,Paul A Ramsland

doi:10.3389/fphar.2017.00393

Abstract

Burkholderia ambifaria is an opportunistic respiratory pathogen belonging to the Burkholderia cepacia complex, a collection of species responsible for the rapidly fatal cepacia syndrome in cystic fibrosis patients. A fucose-binding lectin identified in the B. ambifaria genome, BambL, is able to adhere to lung tissue, and may play a role in respiratory infection. X-ray crystallography has revealed the bound complex structures for four fucosylated human blood group epitopes (blood group B, H type 1, H type 2, and Lex determinants). The present study employed computational approaches, including docking and molecular dynamics (MD), to extend the structural analysis of BambL-oligosaccharide complexes to include four additional blood group saccharides (A, Lea, Leb, and Ley) and a library of blood-group-related carbohydrates. Carbohydrate recognition is dominated by interactions with fucose via a hydrogen-bonding network involving Arg15, Glu26, Ala38, and Trp79 and a stacking interaction with Trp74. Additional hydrogen bonds to non-fucose residues are formed with Asp30, Tyr35, Thr36, and Trp74. BambL recognition is dominated by interactions with fucose, but also features interactions with other parts of the ligands that may modulate specificity or affinity. The detailed computational characterization of the BambL carbohydrate-binding site provides guidelines for the future design of lectin inhibitors.

Highlights

Cystic fibrosis morbidity is mostly due to respiratory infection by opportunistic pathogens (Lyczak et al, 2002; O’Sullivan and Freedman, 2009; Ciofu et al, 2013; Caverly et al, 2015)
To decide which of the crystallographic Burkholderia ambifaria lectin (BambL) receptor structures to use in this study, we compared complex structures predicted by re-docking with respective crystallographic complexes
All blood group saccharides were docked in BambL (PDB ID: 3ZZV) and the top docked poses were analyzed for structural features relevant to recognition (Table 2)

Summary

Introduction

Cystic fibrosis morbidity is mostly due to respiratory infection by opportunistic pathogens (Lyczak et al, 2002; O’Sullivan and Freedman, 2009; Ciofu et al, 2013; Caverly et al, 2015). Burkholderia cepacia is one of the most dangerous pathogens isolated from cystic fibrosis patients; 20% of infected individuals succumb to a rapidly fatal pneumonia termed “cepacia syndrome” (Zahariadis et al, 2003; Blackburn et al, 2004; Lynch, 2009). Burkholderia ambifaria, a member of the B. cepacia complex, has been isolated from both clinical and environmental samples (Coenye et al, 2001). In addition to infecting human respiratory tissue, B. ambifaria can colonize plant rhizospheres, where it promotes growth and protects against invading fungi (Li et al, 2002; Lee et al, 2006; Parra-Cota et al, 2014)

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