Dataset Information

Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, ?-Helix to ?-Sheet Transition, and Formation of ?-Barrel Intermediates.

ABSTRACT: The self-assembly of human islet amyloid polypeptide (hIAPP) into ?-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8-17 as ?-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8-20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-? nanofibrils in silico from isolated helical monomers via the helical oligomers and ?-helices to ?-sheets transition, as confirmed by transmission electron microscopy, atomic force microscopy, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and reversed-phase high performance liquid chromatography. The computational results also suggest that the critical nucleus of aggregation corresponds to hexamers, consistent with a recent mass-spectroscopy study of hIAPP8-20 aggregation. hIAPP8-20 oligomers smaller than hexamers are helical and unstable, while the ?-to-? transition starts from the hexamers. Converted ?-sheet-rich oligomers first form ?-barrel structures as intermediates before aggregating into cross-? nanofibrils. This study uncovers a complete picture of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of ?-barrel intermediates, and assembly of cross-? protofibrils, thereby shedding light on the aggregation of full-length hIAPP, a hallmark of pancreatic beta-cell degeneration.

SUBMITTER: Sun Y

PROVIDER: S-EPMC6499678 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates.

Sun Yunxiang Y Kakinen Aleksandr A Xing Yanting Y Faridi Pouya P Nandakumar Aparna A Purcell Anthony W AW Davis Thomas P TP Davis Thomas P TP Ke Pu Chun PC Ding Feng F

Small (Weinheim an der Bergstrasse, Germany) 20190325 18

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet-rich nanofibrils is associated with the pathogeny of type 2 diabetes. Soluble hIAPP is intrinsically disordered with N-terminal residues 8-17 as α-helices. To understand the contribution of the N-terminal helix to the aggregation of full-length hIAPP, here the oligomerization dynamics of the hIAPP fragment 8-20 (hIAPP8-20) are investigated with combined computational and experimental approaches. hIAPP8-20 forms cross-β nan ...[more]

PMID: 30908844

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Project description:Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type Abeta(17-42) oligomers with different protonation states of Glu(22), as well the E22Q (Dutch) mutants. The association free energy of small beta-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the beta-sheet oligomers. The charge reduction of the wild-type Abeta(17-42) oligomers upon protonation of the solvent-exposed Glu(22) at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type Abeta(17-42) oligomers at neutral pH and the Dutch mutants, on the one hand, and the Abeta(17-42) oligomers with protonated Glu(22), on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp(23) and Lys(28). Peculiarities in the conformational stability and the association thermodynamics for the different models of the Abeta(17-42) oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure.

Dataset Information

Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, ?-Helix to ?-Sheet Transition, and Formation of ?-Barrel Intermediates.

Publications

Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates.

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