Atomistic details on the glycosylation of a peptide

Abstract

Glycosylation significantly influences the properties and functions of peptides by attaching carbohydrate groups to specific amino acids. This modification can enhance peptide stability, solubility, and resistance to enzymatic degradation, while also affecting folding and overall structure.1 There are some contradictory studies suggesting that glycation can enhance peptide–peptide association enthalpy, reduce conformational entropy, and promote β-sheet-rich aggregate formation.2 Driven by such evidence, we performed atomistic MD simulations of a number of peptides derived from the A chain of human insulin, which has been shown to self-assemble. The peptides were glycosylated at different positions as per the suitable sites available. Our study inferred that the interaction between the hydrophobic residues plays a vital role in the aggregation process, as the unglycosylated peptide formed a substantially higher number of hydrophobic contacts, resulting in reduced solvent exposure over time. In contrast, glycosylation decreased the number of such contacts, consistent with reduced aggregation propensity. The Free Energy Landscape displayed two distinct minima separated by an energy barrier, indicating the presence of multiple metastable conformational states associated with aggregation. The monoglycosylated form showed a slight shift in the primary minimum, whereas the di-glycosylated peptide exhibited a single, well-defined minimum, reflecting a simpler and less aggregation-prone conformational ensemble. Glycosylation also influenced peptide translational mobility. Diffusion coefficient indicated nearly a two-fold increase in peptide mobility upon glycosylation. These findings provide molecular-level insights into how glycosylation modulates peptide functional properties, offering a potential design strategy for reducing aggregation in therapeutic peptides through glycosylation.