Glycosylation Enhances Peptide Hydrophobic Collapse by Impairing Solvation

Abstract

Post-translational N-glycosylation of proteins is ubiquitous in eukaryotic cells, and has been shown to influence the thermodynamics of protein collapse and folding. However, the mechanism for this influence is not well understood. All-atom molecular dynamics simulations are carried out to study the collapse of a peptide linked to a single N-glycan. The glycan is shown to perturb the local water hydrogen-bonding network, rendering it less able to solvate the peptide and thus enhancing the hydrophobic contribution to the free energy of collapse. The enhancement of the hydrophobic collapse compensates for the weakened entropic coiling due to the bulky glycan chain and leads to a stronger burial of hydrophobic surface, presumably enhancing folding. This conclusion is reinforced by comparison with coarse-grained simulations, which contain no explicit solvent and correspondingly exhibit no significant thermodynamic changes on glycosylation.

Engineering the Pattern of Protein Glycosylation Modulates the Thermostability of a GH11 Xylanase

“…In silico studies using coarsegrained strategies corroborate the enthalpic stabilization of the Src-SH3 domain by different degrees of glycosylation (22). In contrast, other studies suggest that the stabilization might be due either to a "chaperone-like" activity of glycans (14,17) or to hydrophobic collapse resulting from impaired solvation of the protein (23) and is largely entropic in origin (14,17).…”

“…Molecular modeling methodologies, including MD simulations, are emerging as promising tools for structural and conformational investigations of glycoproteins and glycans with a high degree of accuracy not only in the spatial and time components but also in the prediction of geometry, flexibility, and intermolecular interactions (27,28). Although MD simulation allows a description of the conformational properties of these molecules, only a limited number of glycoproteins have so far been studied using this method (23,29,30). The methylotrophic yeast Pichia pastoris has been widely used as a cellular host for the expression of glycosylated recombinant proteins (31).…”

Specific and Nonspecific Effects of Glycosylation

“…11,52 Prior studies have suggested that carbohydrates may indirectly impact peptide conformation by reorganizing the surrounding solvent structure and, thus, enhancing the hydrophobic driving force for collapse. 14,34,52 Our simulations suggest that disaccharides may have relatively little effect upon the tetrahedral structure of water solvating unfolded peptides. In fact, the disaccharide appeared to have less impact upon the solvation structure than the peptide itself.…”

Food Nanoscience and Nanotechnology

“…This is probably due to its high affinity for the phospholipid cardiolipin in the inner mitochondrial membrane (Prenner et al 1997;Wipf et al 2005). Among the XJB peptides, those that have received more attention are XJB-5-131 and XJB-5-131 which have been shown to exert inhibition against the generation of actinomycin d-induced superoxide and cardiolipin peroxidation (Wipf et al 2005;Cheng et al 2010). XJB-5-131 was efficacious in a hemorrhagic shock rat model (Macias et al 2007) and displayed anti-inflammatory properties in mice (Cheng et al 2010).…”

“…Among the XJB peptides, those that have received more attention are XJB-5-131 and XJB-5-131 which have been shown to exert inhibition against the generation of actinomycin d-induced superoxide and cardiolipin peroxidation (Wipf et al 2005;Cheng et al 2010). XJB-5-131 was efficacious in a hemorrhagic shock rat model (Macias et al 2007) and displayed anti-inflammatory properties in mice (Cheng et al 2010). Recently, the XJB peptides have also been shown to protect cell cultures against radiation damage (Kanai et al 2007;Rajagopalan et al 2009;Cheng et al 2010).…”