IAPP Fibril Formation; A Zipper Story

Amyloid fibrils represent a stable form of many misfolded proteins associated with numerous diseases. A well known example is diabetes type II caused by the Islet amyloid polypeptide. The appearance of IAPP fibrils in pancreatic tissue is a hallmark of diabetes type II. To design therapeutic agents to combat the progression of diabetes type II, it is worthwhile to investigate the mechanisms of the IAPP fibril growth. In this work, we present a systematic study of several methods aimed at investigating how a IAPP fibril grows. A whole length IAPP fibril consists of two interacting β-sheets. The study focuses on the amyloidogenic region of the IAPP fibril, residues 22 to 27 (NFGAIL). We have employed standard molecular dynamics, umbrella sampling, replica exchange umbrella sampling and transition path sampling. Our results indicate that the residues Ala25, Ile26 and Leu27 of the hIAPP are the vital contacts for a monomer to dock to the growing fibril. The data suggests that interaction with the sheet below the sheet that the monomer is attaching to is responsible for this interaction. Another important finding is that by using standard umbrella sampling one runs the risk of encountering trapping effects. This may not always be a problem but when one attempts to extract structural information this may lead to problems. We have shown that by using replica exchange umbrella sampling this trapping does not occur.