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

Paul, Arghadwip; Samantray, Suman; Anteghini, Marco; Strodel, Birgit

doi:10.1101/2020.07.27.223487

Cited by 7 publications

(12 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the peptides prefer extended structures, these are in fact to a large extent poly-proline II (PPII) conformations. This shortcoming of A99-d was already revealed in our previous work 78 and confirmed for Aβ 16−22 here (data not shown). It has been proposed that PPII might prevent the formation of β-sheet 79 due to its particular orientation of the amide bonds.…”

Section: Too Strong Peptide-water Interactions With A99-d In the Case Of A99-d Not Onlysupporting

confidence: 91%

Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations

Samantray

Yin

Kav

et al. 2020

J. Chem. Inf. Model.

Self Cite

110

View full text Add to dashboard Cite

The progress towards understanding the molecular basis of Alzheimers's disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the force fields tested can distinguish between aggregation-prone and non-aggregating peptide sequences, producing the same and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as Aβ were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the Aβ 16−22 peptide and mutations of it as test case. We investigate their performance in modeling the monomeric state, the aggregation into oligomers, and the stability of the aggregation end product, i.e., the fibrillar state. A main finding is that changing the force field has a stronger effect on the simulated aggregation pathway than changing the peptide sequence. Also the new force fields are not able to reproduce the experimental aggregation propensity order of the peptides. Dissecting the various energy contributions shows that AMBER99SB-disp overestimates the interactions between the peptides and water, thereby inhibiting peptide aggregation.More promising results are obtained with CHARMM36m and especially its version with increased protein-water interactions. It is thus recommended to use this force field for peptide aggregation simulations and base future reparameterizations on it. IntroductionIntrinsically disordered proteins (IDPs) are a class of proteins which are either completely unstructured or contain large disordered regions in their native state, which comes with a high tendency towards self-assembly leading to non-toxic or toxic aggregates and fibrils that may be related to diseases. 1 One of the IDPs is the amyloid-beta peptide (Aβ), forming 2

show abstract

Section: Too Strong Peptide-water Interactions With A99-d In the Case Of A99-d Not Onlysupporting

confidence: 91%

Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations

Samantray

Yin

Kav

et al. 2020

J. Chem. Inf. Model.

Self Cite

110

View full text Add to dashboard Cite

show abstract

“…conformations. This shortcoming of A99-d was already revealed in our previous work 78 and confirmed for Aβ 16−22 here (data not shown). It has been proposed that PPII might prevent the formation of β-sheet 79 due to its particular orientation of the amide bonds.…”

Section: Stability Of Preformed Fibrillar Aggregatessupporting

confidence: 91%

“…Also in our benchmark of Aβ 1−40 the performances of C36m and CHARMM22* were quite similar. 78 Future directions The overall conclusion is that the IDP-corrected well as conformational characteristics of the monomeric state, given that the current study showed that the different behaviors of the FFs already emerge for the peptide monomers.…”

Section: Stability Of Preformed Fibrillar Aggregatesmentioning

confidence: 76%

Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations

Samantray

Yin

Kav

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The progress towards understanding the molecular basis of Alzheimers’s disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the force fields tested can distinguish between aggregation-prone and non-aggregating peptide sequences, producing the same and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as Aβ were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the Aβ16−22 peptide and mutations of it as test case. We investigate their performance in modeling the monomeric state, the aggregation into oligomers, and the stability of the aggregation end product, i.e., the fibrillar state. A main finding is that changing the force field has a stronger effect on the simulated aggregation pathway than changing the peptide sequence. Also the new force fields are not able to reproduce the experimental aggregation propensity order of the peptides. Dissecting the various energy contributions shows that AMBER99SB-disp overestimates the interactions between the peptides and water, thereby inhibiting peptide aggregation. More promising results are obtained with CHARMM36m and especially its version with increased protein–water interactions. It is thus recommended to use this force field for peptide aggregation simulations and base future reparameterizations on it.

show abstract

“…To our knowledge, a dimer structure with such a high amount of β-sheet and general order has never been reported before from all-atom MD simulations studying the aggregation of Aβ from disordered monomers into oligomers. We conclude that only the MD sampling of several microseconds and the usage of a force field well suited for Aβ allows the random coil to β-sheet transition to be simulated [78,79]. Thus, with the current simulations we finally open the door to the nucleation process of the amyloid formation becoming observable.…”

Section: Dimerization Of Aβ42 In Solution and At The Neuronal Membranementioning

confidence: 81%

“…For both the dimer in solution and on the membrane considerable β-sheet formation is observed. With the same force field, mostly disordered conformations were sampled for Aβ during a 30 µs MD simulation, with an average β-sheet content of about 15% [79]. This rises to ≈36% for the dimer in solution and 28% for the membrane-adsorbed dimer.…”

Section: Dimerization Of Aβ42 In Solution and At The Neuronal Membranementioning

confidence: 99%

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Fatafta

Khaled

Sayyed-Ahmad

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

The aggregation of amyloid β-peptides into neurotoxic oligomers is a key feature in the development of Alzheimer's disease. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity. To gain a detailed understanding of the mutual effects of amyloid-β oligomers and the neuronal membrane, we carried out a total of 12 μs all-atom molecular dynamics (MD) simulations of the dimerization of the full-length Aβ42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of Aβ42 resulting from its dimerization and interactions with the neuronal membrane are compared to those occurring upon its dimerization in the aqueous phase, which is also tested by 12 μs of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. Aβ42 dimerization in solution, on the other hand, is characterized by a random coil to β-sheet transition that seems to be on-pathway to amyloid aggregation. As the neurotoxic activity of amyloid oligomers increases with oligomer order, the results suggest that GM1 is neuroprotective against Aβ-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.

show abstract

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

Cited by 7 publications

References 66 publications

Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations

Different Force Fields Give Rise to Different Amyloid Aggregation Pathways in Molecular Dynamics Simulations

Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Contact Info

Product

Resources

About