The smaller heparin fragments bind non-specifically through the IAPP sequence: An in silico study

Abstract

The diminishing β-cell mass of pancreas in type II diabetes mellitus (TIIDM) is intricately linked with high fibrillation propensity of islet amyloid polypeptide (IAPP, aka amylin). IAPP is one of the most amyloidogenic peptide secreted by pancreatic β-cells. In the autopsy of TIIDM patients, IAPP rich amyloid plaques are found containing different components of extracellular matrix (ECM), including heparin. For a positively charged IAPP, interaction with heparin which has accessible high density negatively charged functional groups is anticipated to moderate the fibrillation kinetics. Hence, the heparin has shown to affect the amyloidogenicity and cytotoxicity of IAPP depending upon its polymer length; short polymer inhibited the amyloidogenicity and longer fragment enhanced the propensity. Here using docking and molecular dynamic (MD) simulations studies, the work investigates key interactions between IAPP and different heparin fragments, those are likely involved in moderating IAPP fibrillation kinetics in presence of different length heparin fragments. The findings indicate that the heparin fragments of longer length, >dp7, predominantly interact with IAPP N- and C-termini, resulting in a stable complex with solvent accessible self-recognition element (SRE) of IAPP sequence. However, shorter fragment non-specifically binds through the IAPP sequence, including N-terminus residues and SRE sequences.

Keywords: Amyloid; Binding energy; Docking; Heparin; IAPP.