In silico folding and aggregation study of human amylin, an amyloidosis protein
P. Jiang
2011
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Key Takeaway Key Takeaway: This study reveals a dual-path mechanism in human amylin aggregation, suggesting potential therapeutic targets for treating amyloidosis.
Abstract
Abnormal self-assembly of proteins converting their native conformations into ~ sheet rich fibrillar structures is the hallmark of several so called "misfolding diseases" including Type 2 Diabetes Mellitus (T2DM), Alzheimer's and Parkinson's diseases, etc. Human islet amyloid polypeptide (hlAPP or amylin) is the major component of amyloid deposits found in the pancreas of 90% T2DM patients. Although extensive studies have been performed in the recent decades, detailed information 'about hiAPP aggregation and the related pathology remains missing. The aim of this work is to use computational methodologies to understand (1) the mechanism underlying the abnormal structural transition; (2) how the other molecules modulate the process either as catalysts or anti-aggregation factors. Several amyloidogenic segments rather than full-length hlAPP were chosen as peptide models to compare with their nonamyloidogenic counterparts of rodent species. Even for these short peptide models thorough conformational sampling is still a tough issue. Thus an enhanced sampling computational method replica exchange molecular dynamics (REMD), was adopted in most simulations To resolve the multifaceted characteristics of hiAPP aggregation, multiple systems comprising of pure peptide, peptide-lipid, peptide-compound, or peptide-protein have been constructed and undergone extensive simulations. The aggregation behaviors of pure peptides were studied to understand aggregation mechanism and the impacts of sequence variation. In the early stage of peptide aggregation, a dual-path mechanism was clearly observed in our simulations. One path referred to as "reptation ATTENTION: The Singapore Copyright Act applies to the use of this document. Nanyang Technological University Library