Monomer Dynamics of Alzheimer Peptides and Kinetic Control of Early Aggregation in Alzheimer's Disease

Acharya, Srabasti; Srivastava, Kinshuk Raj; Nagarajan, Sureshbabu; Lapidus, Lisa J.

doi:10.1002/cphc.201600706

Cited by 20 publications

(27 citation statements)

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“…Acharya et al (81) have recently investigated the chain dynamics of Ab by monitoring quenching of the triplet state of tryptophan by cysteine. The inferred timescale of the contact formation between residue 4 and residue 35 was several microseconds.…”

Section: Fret Efficiency-lifetime Analysis and Nsfcs Reveal Nanosementioning

confidence: 99%

Highly Disordered Amyloid-β Monomer Probed by Single-Molecule FRET and MD Simulation

Meng

Bellaiche

Kim

et al. 2018

Biophysical Journal

125

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Monomers of amyloid-β (Aβ) protein are known to be disordered, but there is considerable controversy over the existence of residual or transient conformations that can potentially promote oligomerization and fibril formation. We employed single-molecule Förster resonance energy transfer (FRET) spectroscopy with site-specific dye labeling using an unnatural amino acid and molecular dynamics simulations to investigate conformations and dynamics of Aβ isoforms with 40 (Aβ40) and 42 residues (Aβ42). The FRET efficiency distributions of both proteins measured in phosphate-buffered saline at room temperature show a single peak with very similar FRET efficiencies, indicating there is apparently only one state. 2D FRET efficiency-donor lifetime analysis reveals, however, that there is a broad distribution of rapidly interconverting conformations. Using nanosecond fluorescence correlation spectroscopy, we measured the timescale of the fluctuations between these conformations to be ∼35 ns, similar to that of disordered proteins. These results suggest that both Aβ40 and Aβ42 populate an ensemble of rapidly reconfiguring unfolded states, with no long-lived conformational state distinguishable from that of the disordered ensemble. To gain molecular-level insights into these observations, we performed molecular dynamics simulations with a force field optimized to describe disordered proteins. We find, as in experiments, that both peptides populate configurations consistent with random polymer chains, with the vast majority of conformations lacking significant secondary structure, giving rise to very similar ensemble-averaged FRET efficiencies.

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Section: Fret Efficiency-lifetime Analysis and Nsfcs Reveal Nanosementioning

confidence: 99%

Highly Disordered Amyloid-β Monomer Probed by Single-Molecule FRET and MD Simulation

Meng

Bellaiche

Kim

et al. 2018

Biophysical Journal

125

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“…From a FRET study of Aβ40 and Aβ42 it was found that both peptides do not exhibit conformational dynamics exceeding 1 µs, 35 which also agrees with the findings from fluorescence measurements using the method of Trp-Cys contact quenching. 36 Given the simulation length of 30 µs of the MD data generated by D. E. Shaw Research, we use their data (which were kindly provided by them) to assess the kinetics of Aβ40 as sampled by the different FFs.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment

Paul

Samantray

Anteghini

et al. 2020

Preprint

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The amlyoid-β peptide (Aβ) is closely linked to the development of Alzheimer’s disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying the behavior of this peptide at the (sub)molecular level, thereby providing insight into the molecular basis of Alzheimer’s disease. General key aspects of MD simulations are the force field used for modeling the peptide or protein and its environment, which is important for accurate modeling of the system of interest, and the length of the simulations, which determines whether or not equilibrium is reached. In this study we address these points by analyzing 30-µs MD simulations acquired for Aβ40 using seven different force fields. We assess the convergence of these simulations based on the convergence of various structural properties and of NMR and fluorescence spectroscopic observables. Moreover, we calculate Markov state models for each of the seven MD simulations, which provide an unprecedented view of the thermodynamics and kinetics of the amyloid-β peptide. This further allows us to provide answers for pertinent questions, like: Which force fields are suitable for modeling Aβ? (a99SB-UCB and a99SB-ILDN/TIP4P-D); What does Aβ peptide really look like? (mostly extended and disordered) and; How long does it take MD simulations of Aβ to attain equilibrium? (20–30 µs). We believe the analyses presented in this study will provide a useful reference guide for important questions relating to the structure and dynamics of Aβin particular, and by extension other similar disordered peptides.

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“…Many studies of different unfolded proteins have revealed a wide range of diffusion coefficients depending on sequence, pH and other solvent conditions [5–11]. For example, the intramolecular diffusion coefficient of the Alzheimer’s peptide lacking residues 41 and 42 (Aβ40) was five times faster than the Alzheimer’s peptide containing those residues (Aβ42) [12]. This 5-fold change in intramolecular diffusion rate correlates with the difference in lag time of aggregation for Aβ40 vs. Aβ42, which suggests that aggregation is kinetically controlled by the reconfiguration of the monomer.…”

Section: Introductionmentioning

confidence: 99%

Intramolecular diffusion controls aggregation of the PAPf39 peptide

Srivastava

French

Tzul

et al. 2016

Biophysical Chemistry

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The 39-residue fragment of human prostatic acidic phosphatase (PAP) is found in high concentrations in semen and easily form fibrils. Previous work has shown that fibrillization is accelerated with a deletion of the first 8, mostly charged residues and it was hypothesized that fibrillization depended on the dynamics of these peptides. To test this hypothesis we have measured the intramolecular diffusion of the full length and 8-residue deletion peptides at two different pHs and found a correlation with fibrillization lag time. These results can be explained by a simple kinetic model of the early stages of aggregation in which oligomerization is controlled by the rate of peptide reconfiguration.

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Monomer Dynamics of Alzheimer Peptides and Kinetic Control of Early Aggregation in Alzheimer's Disease

Cited by 20 publications

References 50 publications

Highly Disordered Amyloid-β Monomer Probed by Single-Molecule FRET and MD Simulation

Highly Disordered Amyloid-β Monomer Probed by Single-Molecule FRET and MD Simulation

Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment

Intramolecular diffusion controls aggregation of the PAPf39 peptide

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