title: Effect of proline mutations on the monomer conformations of amylin.
abstract: The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic β-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate β-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various β-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long β-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit β conformations and stabilize the α-helical conformation. Fewer substitutions do not have a significant inhibiting effect.
authors.affiliation: Materials Science Division, Argonne National Laboratory, Argonne, Illinois, USA.
authors.forename: Chi-cheng
authors.initials: CC
authors.lastname: Chiu
authors.forename: Sadanand
authors.initials: S
authors.lastname: Singh
authors.forename: Juan J
authors.initials: JJ
authors.lastname: de Pablo
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D011392:Proline; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D058228:Islet Amyloid Polypeptide; D050505:Mutant Proteins; D011392:Proline; C105254:pramlintide