Simulated Dynamics of Glycans on Ligand-Binding Domain of NMDA Receptors Reveals Strong Dynamic Coupling between Glycans and Protein Core
Autor: | Anton V. Sinitskiy, Vijay S. Pande |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Glycan Time Factors Protein subunit Molecular Conformation Molecular Dynamics Simulation Ligands Receptors N-Methyl-D-Aspartate 03 medical and health sciences Molecular dynamics 0302 clinical medicine Polysaccharides Animals Humans Physical and Theoretical Chemistry Receptor biology Chemistry Dynamics (mechanics) Potentiator Ligand binding domain Computer Science Applications carbohydrates (lipids) 030104 developmental biology nervous system Biochemistry Biophysics biology.protein NMDA receptor 030217 neurology & neurosurgery Protein Binding |
Zdroj: | Journal of Chemical Theory and Computation. 13:5496-5505 |
ISSN: | 1549-9626 1549-9618 |
Popis: | N-Methyl-d-aspartate (NMDA) receptors, key neuronal receptors playing the central role in learning and memory, are heavily glycosylated in vivo. Astonishingly little is known about the structure, dynamics, and physiological relevance of glycans attached to them. We recently demonstrated that certain glycans on the ligand binding domain (LBD) of NMDA receptors (NMDARs) can serve as intramolecular potentiators, changing EC50 of NMDAR coagonists. In this work, we use molecular dynamics trajectories, in aggregate 86.5 μs long, of the glycosylated LBD of the GluN1 subunit of the NMDAR to investigate the behavior of glycans on NMDARs. Though all glycans in our simulations were structurally the same (Man5), the dynamics of glycans at different locations on NMDARs was surprisingly different. The slowest-time scale motions that we detected in various glycans in some cases corresponded to a flipping of parts of glycans relative to each other, while in other cases they reduced to a head-to-tail bending of a glycan. We predict that time scales of conformational changes in glycans on the GluN1 LBD of NMDARs range from nanoseconds to at least hundreds of microseconds. Some of the conformational changes in the glycans correlate with the physiologically important clamshell-like opening and closing of the GluN1 LBD domain. Thus, glycans are an integral part of NMDARs, and computational models of NMDARs should include glycans to faithfully represent the structure and the dynamics of these receptors. |
Databáze: | OpenAIRE |
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