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Simulation of carbohydrate-protein interactions: Computer-aided design of a second generation GM1 mimic

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Abstract

The oligosaccharide of ganglioside GM1 [Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-1Cer] is the cellular target of two bacterial enterotoxins: the cholera toxin (CT) and the heat-labile toxin of E.coli (LT). We recently reported that the pseudosaccharide 2[Galβ1-3GalNAcβ1-4(NeuAcα2-3)DCCHD] is a high-affinity ligand for CT, and thus a functional mimic of GM1 (Bernardi, A., Checchia, A., Brocca, P., Sonnino, S. and Zuccotto, F., J. Am. Chem. Soc., 121 (1999) 2032–2036). In this paper we describe the design of a second-generation mimic, formally obtained from 2 by inverting the configuration of a single stereocenter, thus transforming a N-acetyl galactosamine into a N-acetyl glucosamine. The design process involved modeling of the free ligand and its LT complex, followed by qualitative and quantitative comparison with the corresponding structures of 2. The protocol employed relied on both conformational search and molecular dynamics methodologies to account for the flexibility of both the ligand and the protein receptor. The conformational search of the LT:inhibitor complex showed that, compared to 2, the new compound can insert one more hydroxy group within the protein binding site. Molecular dynamics simulations showed that, in turn, this may trigger a series of rearrangements and reorientations of side chains and crystallographic water molecules in the toxin, leading to new H-bond contacts which may result in enhanced affinity of the new inhibitor. FEP calculations were performed by mutating the structure of 2 in solution and in the protein complex, and the prediction was made that the second-generation mimic should be a stronger binder than its parent compound.

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Authors and Affiliations

  1. Dipartimento di Chimica Organica e Industriale, Universita' di Milano and Centro CNR per lo Studio delle Sostanze Organiche Naturali, via Venezian 21, 20133, Milano, Italy

    Anna Bernardi, Marta Galgano & Laura Belvisi

  2. Istituto CNR di Biocatalisi e Riconoscimento Molecolare, via M. Bianco 9, 20133, Milano, Italy

    Giorgio Colombo

Authors
  1. Anna Bernardi
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  2. Marta Galgano
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  3. Laura Belvisi
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  4. Giorgio Colombo
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Bernardi, A., Galgano, M., Belvisi, L. et al. Simulation of carbohydrate-protein interactions: Computer-aided design of a second generation GM1 mimic. J Comput Aided Mol Des 15, 117–128 (2001). https://doi.org/10.1023/A:1008145830153

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