@inproceedings{KangBarbirzGohlkeetal.2014,
  author    = {Kang, Yu and Barbirz, Stefanie and Gohlke, Ulrich and Santer, Mark},
  title     = {Molecular dynamics study on the interaction of O-antigen polysaccharides of the gram-negative bacterium Shigella flexneri with the tail-spike-protein of bacteriophage Sf6},
  series = {Abstracts of papers : joint conference / The Chemical Institute of Cananda, CIC, American Chemical Society, ACS},
  volume    = {248},
  booktitle = {Abstracts of papers : joint conference / The Chemical Institute of Cananda, CIC, American Chemical Society, ACS},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {0065-7727},
  pages     = {1},
  year      = {2014},
  language  = {en}
}
@article{KangGohlkeEngstroemetal.2016,
  author    = {Kang, Yu and Gohlke, Ulrich and Engstr{\"o}m, Olof and Hamark, Christoffer and Scheidt, Tom and Kunstmann, Ruth Sonja and Heinemann, Udo and Widmalm, G{\"o}ran and Santer, Mark and Barbirz, Stefanie},
  title     = {Bacteriophage Tailspikes and Bacterial O-Antigens as a Model System to Study Weak-Affinity Protein-Polysaccharide Interactions},
  series = {Journal of the American Chemical Society},
  volume    = {138},
  journal   = {Journal of the American Chemical Society},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {0002-7863},
  doi       = {10.1021/jacs.6b00240},
  pages     = {9109 -- 9118},
  year      = {2016},
  abstract  = {Understanding interactions of bacterial surface polysaccharides with receptor protein scaffolds is important for the development of antibiotic therapies. The corresponding protein recognition domains frequently form low-affinity complexes with polysaccharides that are difficult to address with experimental techniques due to the conformational flexibility of the polysaccharide. In this work, we studied the tailspike protein (TSP) of the bacteriophage Sf6. Sf6TSP binds and hydrolyzes the high-rhamnose, serotype Y O-antigen polysaccharide of the Gram-negative bacterium Shigella flexneri (S. flexneri) as a first step of bacteriophage infection. Spectroscopic analyses and enzymatic cleavage assays confirmed that Sf6TSP binds long stretches of this polysaccharide. Crystal structure analysis and saturation transfer difference (STD) NMR spectroscopy using an enhanced method to interpret the data permitted the detailed description of affinity contributions and flexibility in an Sf6TSP-octasaccharide complex. Dodecasaccharide fragments corresponding to three repeating units of the O-antigen in complex with Sf6TSP were studied computationally by molecular dynamics simulations. They showed that distortion away from the low-energy solution conformation found in the octasaccharide complex is necessary for ligand binding. This is in agreement with a weak-affinity functional polysaccharide protein contact that facilitates correct placement and thus hydrolysis of the polysaccharide close to the catalytic residues. Our simulations stress that the flexibility of glycan epitopes together with a small number of specific protein contacts provide the driving force for Sf6TSP-polysaccharide complex formation in an overall weak-affinity interaction system.},
  language  = {en}
}
@article{KunstmannGohlkeBroekeretal.2018,
  author    = {Kunstmann, Ruth Sonja and Gohlke, Ulrich and Br{\"o}ker, Nina Kristin and Roske, Yvette and Heinemann, Udo and Santer, Mark and Barbirz, Stefanie},
  title     = {Solvent networks tune thermodynamics of oligosaccharide complex formation in an extended protein binding site},
  series = {Journal of the American Chemical Society},
  volume    = {140},
  journal   = {Journal of the American Chemical Society},
  number    = {33},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {0002-7863},
  doi       = {10.1021/jacs.8b03719},
  pages     = {10447 -- 10455},
  year      = {2018},
  abstract  = {The principles of protein-glycan binding are still not well understood on a molecular level. Attempts to link affinity and specificity of glycan recognition to structure suffer from the general lack of model systems for experimental studies and the difficulty to describe the influence of solvent. We have experimentally and computationally addressed energetic contributions of solvent in protein-glycan complex formation in the tailspike protein (TSP) of E. coli bacteriophage HK620. HK620TSP is a 230 kDa native trimer of right-handed, parallel beta-helices that provide extended, rigid binding sites for bacterial cell surface O-antigen polysaccharides. A set of high affinity mutants bound hexa- or pentasaccharide O-antigen fragments with very similar affinities even though hexasaccharides introduce an additional glucose branch into an occluded protein surface cavity. Remarkably different thermodynamic binding signatures were found for different mutants; however, crystal structure analyses indicated that no major oligosaccharide or protein topology changes had occurred upon complex formation. This pointed to a solvent effect. Molecular dynamics simulations using a mobility-based approach revealed an extended network of solvent positions distributed over the entire oligosaccharide binding site. However, free energy calculations showed that a small water network inside the glucose-binding cavity had the most notable influence on the thermodynamic signature. The energy needed to displace water from the glucose binding pocket depended on the amino acid at the entrance, in agreement with the different amounts of enthalpy-entropy compensation found for introducing glucose into the pocket in the different mutants. Studies with small molecule drugs have shown before that a few active water molecules can control protein complex formation. HK620TSP oligosaccharide binding shows that similar fundamental principles also apply for glycans, where a small number of water molecules can dominate the thermodynamic signature in an extended binding site.},
  language  = {en}
}