Exploring the role of hydration and confinement in the aggregation of amyloidogenic peptides Aβ16−22 and Sup357−13 in AOT reverse micelles

Abstract

Knowledge of how intermolecular interactions of amyloid-forming proteins cause protein aggregation and how those interactions are affected by sequence and solution conditions is essential to our understanding of the onset of many degenerative diseases. Of particular interest is the aggregation of the amyloid-β (Aβ) peptide, linked to Alzheimer's disease, and the aggregation of the Sup35 yeast prion peptide, which resembles the mammalian prion protein linked to spongiform encephalopathies. To facilitate the study of these important peptides, experimentalists have identified small peptide congeners of the full-length proteins that exhibit amyloidogenic behavior, including the KLVFFAE sub-sequence, Aβ 16−22 , and the GNNQQNY subsequence, Sup35 7−13 . In this study, molecular dynamics simulations were used to examine these peptide fragments encapsulated in reverse micelles (RMs) in order to identify the fundamental principles that govern how sequence and solution environment influence peptide aggregation. Aβ 16−22 and Sup35 7−13 are observed to organize into anti-parallel and parallel β-sheet arrangements. Confinement in the sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelles is shown to stabilize extended peptide conformations and enhance peptide aggregation. Substantial fluctuations in the reverse micelle shape are observed, in agreement with earlier studies. Shape fluctuations are found to facilitate peptide solvation through interactions between the peptide and AOT surfactant, including direct interaction between non-polar peptide residues and the aliphatic surfactant tails. Computed amide I IR spectra are compared with experimental spectra and found to reflect changes in the peptide structures induced by confinement in the RM environment. Furthermore, examination of the rotational anisotropy decay of water in the RM demonstrates that the water dynamics are sensitive to the presence of peptide as well as the peptide sequence. Overall, our results demonstrate that the RM is a complex confining environment where substantial direct interaction between the surfactant and peptides plays an important role in determining the resulting ensemble of peptide conformations. By extension the results suggest that similarly complex sequence-dependent interactions may determine conformational ensembles of amyloid-forming peptides in a cellular environment. © 2014 AIP Publishing LLC.

Prediction of a stable associated liquid of short amyloidogenic peptides

“…For instance, the presence of molecular crowders may have broad implications for the kinetics and thermodynamics of aggregation 74,75. Downloaded by West Virginia University Libraries on 12/04/2015 18:27:56.also take into account the environment of the oligomers.…”

Amyloid Fibril Nucleation in Reverse Micelles

“…Simulations were performed as NPT ensembles with NAMD 2.9 (Phillips et al, 2005), the CHARMM27 all atom force field for proteins and lipids (Foloppe & MacKerell, Jr., 2000), and TIP3P water (Jorgensen, Chandrasekhar, Madura, Impey, & Klein, 1983). Parameters for the AOT anion and isooctane (isoO) were obtained from previously published studies (Abel et al, 2004;Abel et al, 2010;Tian & Garcia, 2011a;Martinez, Malolepsza, Rivera, Lu, & Straub, 2014a). Long-range electrostatic forces were calculated with the Particle Mesh Ewald method (Darden et al, 1993) and an interaction cutoff of 12 Å was applied within periodic boundary conditions.…”

“…There are significant differences in the interpretation of RM properties, with or without protein inside, in the literature. Although many experimental studies are interpreted with the assumption of an idealized spherical geometry of the RM, most computational studies support the conclusion that encapsulated materials do not experience the conditions of a hard spherical confinement (Abel et al, 2010;Martinez et al, 2014a). Moreover, encapsulated material will likely increase the volume and surface area of an RM.…”

“…All minimizations and all equilibration simulations were performed with NAMD2.9 (Phillips et al, 2005) and the CHARMM27 all atom force field for proteins and lipids (Foloppe & MacKerell, Jr., 2000). Parameters for the AOT anion and isoO were obtained from previously published studies (Abel et al, 2004;Abel et al, 2010;Tian & Garcia, 2011b;Martinez, Malolepsza, Rivera, Lu, & Straub, 2014b). Production runs were either performed on a local 32-node Linux cluster using NAMD2.9 or on 512-node Anton supercomputer for molecular dynamics (Shaw, Dror, Salmon, & Grossman, 2009).…”

Characterization of dynamics and mechanism in the self-assembly of AOT reverse micelles

“…40 Straub and co-workers explored the effect of charged and zwitterionic termini on a RM-spanning protein on the structure and dynamics of RMs 41 as well as the effect of RM-encapsulation on amyloidogenic peptide aggregation. 42 Eskici and Axelsen also investigated the role of RM-encapsulation on the structure of amyloid beta. 43 Molecular simulation has also been used to study the microscopic mechanism of self-assembly and the dynamics of water within RM systems.…”