Computational modelling of protein fibrillation with application to glucagon
A computational method to model the steric zipper of amyloid fibrils (FibPreditor) is developed. The method generates an ensemble of structures for the steric zipper by a number of geometric operations and presents the most energetically favorable candidates as models of steric zipper. The method is shown to successfully reproduce a number of experimentally determined fibril structures. FibPredictor is then applied to model the steric zipper of glucagon fibrils. Phosphate ester derivatives of glucagon are designed based on these models as soluble and stable prodrugs or active alternatives for glucagon. A number of penta-peptide chaperones are also designed as excipients to delay glucagon fibrillation. Although penta-peptides can delay glucagon fibrillation, they are less effective compared to phosphorylation of glucagon.
Topp, Purdue University.
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