Specific and Nonspecific Effects of Glycosylation

Glycosylation regulates vital cellular processes and
dramatically
influences protein folding and stability. In particular, experiments
have demonstrated that asparagine (N)-linked disaccharides drive a
“conformational switch” in a model peptide. The present
work investigates this conformational switch via extensive atomically
detailed replica exchange molecular dynamics simulations in explicit
solvent. To distinguish the effects of specific and nonspecific interactions
upon the peptide conformational ensemble, these simulations considered
model peptides that were N-linked to a disaccharide and to a steric
crowder of the same shape. The simulations are remarkably consistent
with experiment and provide detailed insight into the peptide structure
ensemble. They suggest that steric crowding by N-linked disaccharides
excludes extended conformations, but does not significantly impact
the tetrahedral structure of the surrounding solvent or otherwise
alter the peptide free energy surface. However, the combination of
steric crowding with specific hydrogen bonds and hydrophobic stacking
interactions more dramatically impacts the peptide ensemble and stabilizes
new structures.