Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide

Abstract

A direct observation of amyloid aggregation from isolated peptides to cross-β fibrils is crucial for understanding the nucleation-dependence process, but the corresponding macroscopic timescales impose a major computational challenge. Using rapid all-atom discrete molecular dynamics simulations, we capture the oligomerization and fibrillization dynamics of the amyloid core sequences of amyloid-β (Aβ) in Alzheimer’s disease and islet amyloid polypeptide (IAPP) in type-2 diabetes, namely Aβ16–22 and IAPP22–28. Both peptides and their mixture spontaneously assemble into cross-β aggregates in silico, but follow distinct pathways. Aβ16–22 is highly aggregation-prone with a funneled free energy basin toward multi-layer β-sheet aggregates. IAPP22–28, on the other hand, features the accumulation of unstructured oligomers before the nucleation of β-sheets and growth into double-layer β-sheet aggregates. In the presence of Aβ16–22, the aggregation of IAPP22–28 is promoted by forming co-aggregated multi-layer β-sheets. Our study offers a detailed molecular insight to the long-postulated oligomerization-nucleation process in the amyloid aggregations.

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

“…To characterize oligomerization dynamics, we defined an oligomer as an aggregate of peptides interconnected by at least one intermolecular heavy atoms contact with a cutoff distance of 0.55 nm, and the size as the number of peptides in the complex . Using the last 200 ns trajectories of all independent simulations for a system, we computed the mass‐weighted size distribution of oligomers (Figure d), which corresponded to the probability of finding a peptide in an oligomer of a given size.…”

“…Details of DMD Simulations : All simulations were performed at 300 K by using the DMD algorithm, where the continuous potential functions in classic MD were modeled by discrete step‐wise functions. With significantly enhanced sampling efficiency, DMD simulation were widely used by in studying protein folding, amyloid aggregation, and nanoparticle peptides interactions . The Medusa forcefield adopted in DMD was similar to that used in MD simulation and were fully discussed in the previous studies .…”

“…With significantly enhanced sampling efficiency, DMD simulation were widely used by in studying protein folding, amyloid aggregation, and nanoparticle peptides interactions . The Medusa forcefield adopted in DMD was similar to that used in MD simulation and were fully discussed in the previous studies . Both bonded interactions (i.e., covalent bonds, bond angles, and dihedrals) and nonbonded interactions (i.e., van der Waals, solvation, hydrogen bond, and electrostatic terms) were included.…”

“…Analysis Methods : The secondary structure of hIAPP8‐20 oligomer was determined by using the dictionary secondary structure of protein method . Following the prior work, two chains were considered to form a β‐sheet if i) at least two consecutive residues in each chain adopted the β‐strand conformation and ii) they formed at least two backbone hydrogen bonds. A hydrogen bond was considered to be formed if the distance between backbone N and O atoms was ≤3.5 Å and the angle of N−H···O ≥120° .…”

“…In this work, we employed MD simulations with complementary transmission electron microscopy (TEM), AFM, circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and reversed‐phase high performance liquid chromatography (RP‐HPLC) to investigate the oligomerization and fibrillization dynamics of hIAPP8‐20. Atomistic discrete molecular dynamics (DMD) simulations with implicit solvent—a rapid and accurate MD algorithm widely used to study protein dynamics, protein folding, and aggregation—were performed to study the assembly dynamics up to 20 hIAPP8‐20 peptides. Our simulation results revealed that helical hIAPP8‐20 monomers first assembled into various helix‐rich oligomers from dimers to decomers by burying the hydrophobic surface of the amphiphilic helices.…”