Premium
Pinpointing Proline Substitution to be Responsible for the Loss of Amyloidogenesis in IAPP
Author(s) -
Chakraborty Sandipan,
Mukherjee Barnali,
Basu Soumalee
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12172
Subject(s) - proline , fibril , amyloid (mycology) , chemistry , amyloid fibril , mutation , peptide , valine , biochemistry , amino acid , biophysics , biology , amyloid β , medicine , gene , inorganic chemistry , disease
Human islet amyloid polypeptide ( hIAPP ) is highly amyloidogenic, whereas its homologs in rodents are non‐amyloidogenic. This observed non‐amyloidogenecity of rodent IAPP has been attributed to substitutions by proline in a region of IAPP that forms the core of the fibril. By employing molecular dynamics simulation, we have analyzed effects of position‐specific proline substitution on amyloidogenesis of the core region of the hIAPP fibril (22–28). We depict that substitution to proline at the 25th position is primarily responsible for the loss of amyloidogenecity of the peptide. In addition, 25th and 26th double mutation to proline and valine has been observed to show significant fibril destabilizing ability. On the contrary, substitution at 28th position to proline has the least ability to destabilize the amyloid fibril. Results obtained from this study are particularly important to design variants of the existing antihyperglycemic drug with minimalistic mutation approach for use in patients with diabetes.