Complete characterization of the mutation landscape reveals the effect on amylin stability and amyloidogenicity.

摘要: Type-II diabetes is believed to be partially aggravated by the emergence of toxic amylin protein deposits in extracellular space pancreas β-cells. Amylin, regulatory hormone that co-secreted with insulin, has been observed misfold into structures. Pramlintide, an FDA approved injectable analog mutated at positions 25, 28, and 29 was therefore developed create a more stable, soluble, less-aggregating, equipotent peptide used as adjunctive therapy for diabetes. However, because Pramlintide not ideal, researchers have exploring other analogs therapeutic replacements. In this work, we assist finding optimal computationally revealing mutational landscape amylin. We computed structure energies all possible single-point mutations studied effect they on stability amyloidogenicity. Each 37 residues silico 19 canonical amino acids energy function computing Lennard–Jones, Coulomb solvation analyze changes stability. The mutation identified amylin's conserved stable regions, can tweaked further stabilize structure, regions are susceptible mutations, amyloidogenic. data generate estimations higher-order multiple-point landscapes discovered millions three-point less amyloidogenic than Pramlintide. provided explanation S20G Q10R onset Chinese Maori populations, respectively. Proteins 2015; 83:1014–1026. © 2015 Wiley Periodicals, Inc.