title: Glycosylation May Reduce Protein Thermodynamic Stability by Inducing a Conformational Distortion.
abstract: Glycosylation plays not only a functional role but can also modify the biophysical properties of the modified protein. Usually, natural glycosylation results in protein stabilization; however, in vitro and in silico studies showed that sometimes glycosylation results in thermodynamic destabilization. Here, we applied coarse-grained and all-atom molecular dynamics simulations to understand the mechanism underlying the loss of stability of the MM1 protein by glycosylation. We show that the origin of the destabilization is a conformational distortion of the protein caused by the interaction of the monosaccharide with the protein surface. Though glycosylation creates new short-range glycan-protein interactions that stabilize the conjugated protein, it breaks long-range protein-protein interactions. This has a destabilizing effect because the probability of long- and short-range interactions forming differs between the folded and unfolded states. The destabilization originates not from simple loss of interactions but due to a trade-off between the short- and long-range interactions.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science , Rehovot 76100, Israel.
authors.forename: Yulian
authors.initials: Y
authors.lastname: Gavrilov
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science , Rehovot 76100, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Shental-Bechor
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science , Rehovot 76100, Israel.
authors.forename: Harry M
authors.initials: HM
authors.lastname: Greenblatt
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science , Rehovot 76100, Israel.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Levy
mesh_terms: D006031:Glycosylation; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011328:Prions / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D011328:Prions
keywords: Protein folding; coarse-grained model; protein glycosylation; protein modifications; unfolded state