Abstract
Insulin has been commonly adopted as a peptide drug to treat diabetes given its ability to facilitate
the uptake of glucose from the blood. The development of oral insulin remains elusive over decades
owing to its susceptibility to the enzymes in the gastrointestinal tract and poor permeability through the
intestinal epithelium upon dimerization. Recent experimental studies have revealed that certain O-linked
glycosylation patterns could enhance insulin’s proteolytic stability and reduce its dimerization propensity,
but the understanding of such phenomena at the molecular level is still evasive. To address this challenge,
we propose and test several structural determinants that could potentially in uence insulin’s proteolytic stability
and dimerization propensity. We used these as the metrics to assess the properties of interest from
10 s aggregate molecular dynamics of each of 12 targeted insulin glyco-variants from multiple wild-type
crystal structures. We found that glycan-involved hydrogen bonds and glycan-dimer occlusion were useful
metrics predicting the proteolytic stability and dimerization propensity of insulin, as was in part the solvent
accessible surface area of proteolytic sites, while other plausible metrics were not generally predictive. This
work helps better explain how O-linked glycosylation in uences the proteolytic stability and monomeric
propensity of insulin, illuminating a path towards rational molecular design of insulin glycoforms.
Supplementary materials
Title
Supporting Information: Identifying signatures of proteolytic stability and monomeric propensity in O-glycosylated insulin using molecular simulation
Description
This contains the supplemental tables (5) and figures (3) for the paper: Identifying signatures of proteolytic
stability and monomeric propensity in O-glycosylated insulin
using molecular simulation.
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