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Conformational flexibility of N-glycans in solution studied by REMD simulations

Abstract

Protein–glycan recognition regulates a wide range of biological and pathogenic processes. Conformational diversity of glycans in solution is apparently incompatible with specific binding to their receptor proteins. One possibility is that among the different conformational states of a glycan, only one conformer is utilized for specific binding to a protein. However, the labile nature of glycans makes characterizing their conformational states a challenging issue. All-atom molecular dynamics (MD) simulations provide the atomic details of glycan structures in solution, but fairly extensive sampling is required for simulating the transitions between rotameric states. This difficulty limits application of conventional MD simulations to small fragments like di- and tri-saccharides. Replica-exchange molecular dynamics (REMD) simulation, with extensive sampling of structures in solution, provides a valuable way to identify a family of glycan conformers. This article reviews recent REMD simulations of glycans carried out by us or other research groups and provides new insights into the conformational equilibria of N-glycans and their alteration by chemical modification. We also emphasize the importance of statistical averaging over the multiple conformers of glycans for comparing simulation results with experimental observables. The results support the concept of “conformer selection” in protein–glycan recognition.

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Acknowledgements

This research was supported in part by a Grant for Scientific Research on a Priority Area ‘Transient macromolecular complex’ (to Y.S.), the Development and Use of the Next-Generation Supercomputer Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Y.S.), the Fund for Seeds of Collaborative Research of the RIKEN (to Y.Y., Y.S., and S.R.), and the Fund from the High Performance Computing Infrastructure (HPCI) Strategic Program of MEXT (to Y.S.). We also thank the RIKEN Integrated Cluster of Clusters (RICC) for providing computational resources.

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Correspondence to Yuji Sugita.

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Special issue: Computational Biophysics

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Re, S., Nishima, W., Miyashita, N. et al. Conformational flexibility of N-glycans in solution studied by REMD simulations. Biophys Rev 4, 179–187 (2012). https://doi.org/10.1007/s12551-012-0090-y

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Keywords

  • N-glycan
  • Conformational flexibility
  • Protein–glycan interactions
  • N-glycan modifications
  • Conformer selection
  • Molecular dynamics simulations
  • Replica-exchange molecular dynamics simulations