title: Complete characterization of the mutation landscape reveals the effect on amylin stability and amyloidogenicity.
abstract: Type-II diabetes is believed to be partially aggravated by the emergence of toxic amylin protein deposits in the extracellular space of the pancreas β-cells. Amylin, the regulatory hormone that is co-secreted with insulin, has been observed to misfold into toxic structures. Pramlintide, an FDA approved injectable amylin analog mutated at positions 25, 28, and 29 was therefore developed to create a more stable, soluble, less-aggregating, and equipotent peptide that is used as an adjunctive therapy for diabetes. However, because Pramlintide is not ideal, researchers have been exploring other amylin analogs as therapeutic replacements. In this work, we assist the finding of optimal analogs by computationally revealing the mutational landscape of amylin. We computed the structure energies of all possible single-point mutations and studied the effect they have on amylin stability and amyloidogenicity. Each of the 37 amylin residues was mutated in silico into the 19 canonical amino acids and an energy function computing the Lennard-Jones, Coulomb and solvation energy was used to analyze changes in stability. The mutation landscape identified amylin's conserved stable regions, residues that can be tweaked to further stabilize structure, regions that are susceptible to mutations, and mutations that are amyloidogenic. We used the single-point mutational landscape data to generate estimations for higher-order multiple-point mutational landscapes and discovered millions of three-point mutations that are more stable and less amyloidogenic than Pramlintide. The landscapes provided an explanation for the effect of the S20G and Q10R mutations on the onset of diabetes of the Chinese and Maori populations, respectively.
authors: School of Computer Science, McGill University, Montreal, Quebec, Canada.|McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.
authors: Mohamed Raef
authors: MR
authors: Smaoui
authors: School of Computer Science, McGill University, Montreal, Quebec, Canada.|McGill Center for Bioinformatics, McGill University, Montreal, Quebec, Canada.
authors: Jérôme
authors: J
authors: Waldispühl
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008322:Mammals; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D055550:Protein Stability; D020539:Sequence Analysis, Protein / Q000379:methods
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; C105254:pramlintide
keywords: amylin; amyloidogenicity; diabetes; landscape; mutations; pramlintide