Title:
Developing molecular dynamics-based screening methods for identifying O-glycosylated insulin analogs with enhanced proteolytic stability and monomeric propensity
Developing molecular dynamics-based screening methods for identifying O-glycosylated insulin analogs with enhanced proteolytic stability and monomeric propensity
Time:
05/28/2022 07:00 PM PDT
05/28/2022 08:00 PM MDT
05/28/2022 07:00 PM PDT
05/28/2022 08:00 PM MDT
05/28/2022 09:00 PM CDT
05/28/2022 10:00 PM EDT
05/28/2022 10:00 PM EDT
05/29/2022 03:00 AM BST
05/29/2022 04:00 AM CEST
05/29/2022 10:00 AM Taiwan
05/29/2022 10:00 AM Taiwan
Field:
Biophysics, computational chemistry
Biophysics, computational chemistry
Sub-field:
molecular dynamics
Supplementary keywords:
molecular dynamics, insulin, O-glycosylation, protein degradation, protein design
molecular dynamics
Supplementary keywords:
molecular dynamics, insulin, O-glycosylation, protein degradation, protein design
Abstract:
In the United States, over 7 million people use insulin as a peptide drug to treat diabetes given its ability to promote the glucose absorption from the blood into liver. While oral insulin drugs are highly desirable due to their non-invasive nature, their development is limited by their 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. In addition, the enormous efforts required for chemical synthesis and characterization make fast screening of insulin glycoform candidates nearly impossible.
To address this challenge, we propose and test several structural determinants that could potentially enhance insulin’s proteolytic stability and monomeric propensity. We used these as the metrics to assess the properties of interest from 10-microsecond 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 influences the proteolytic stability and monomeric propensity of insulin, illuminating a path towards rational molecular design of insulin glycoforms.
In the United States, over 7 million people use insulin as a peptide drug to treat diabetes given its ability to promote the glucose absorption from the blood into liver. While oral insulin drugs are highly desirable due to their non-invasive nature, their development is limited by their 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. In addition, the enormous efforts required for chemical synthesis and characterization make fast screening of insulin glycoform candidates nearly impossible.
To address this challenge, we propose and test several structural determinants that could potentially enhance insulin’s proteolytic stability and monomeric propensity. We used these as the metrics to assess the properties of interest from 10-microsecond 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 influences the proteolytic stability and monomeric propensity of insulin, illuminating a path towards rational molecular design of insulin glycoforms.
No comments:
Post a Comment