Elsevier

Biophysical Chemistry

Volume 264, September 2020, 106421
Biophysical Chemistry

Structures of the intrinsically disordered Aβ, tau and α-synuclein proteins in aqueous solution from computer simulations

https://doi.org/10.1016/j.bpc.2020.106421Get rights and content

Highlights

  • IDPs are involved in neurodegenerative diseases.

  • Structure determination of the Aβ, tau and α-synuclein proteins is a challenge.

  • Computer simulation results free or guided by experimental data.

  • PEP-fold results on α-synuclein monomer.

Abstract

Intrinsically disordered proteins (IDPs) play many biological roles in the human proteome ranging from vesicular transport, signal transduction to neurodegenerative diseases. The Aβ and tau proteins, and the α-synuclein protein, key players in Alzheimer’s and Parkinson’s diseases, respectively are fully disordered at the monomer level. The structural heterogeneity of the monomeric and oligomeric states and the high self-assembly propensity of these three IDPs have precluded experimental structural determination. Simulations have been used to determine the atomic structures of these IDPs. In this article, we review recent computer models to capture the equilibrium ensemble of Aβ, tau and α-synuclein proteins at different association steps in aqueous solution and present new results of the PEP-FOLD framework on α-synuclein monomer.

Section snippets

1 1 Introduction

Intrinsically disordered proteins (IDPs) play key roles in many cellular processes, such as vesicular transport, signal transduction, and neurogenerative diseases. While some IDPs have disordered and flexible regions important for protein–protein, protein-RNA and protein-DNA functions, others do not adopt a well-defined three-dimensional (3D) structure with a funnel-like free energy landscape [1]. Rather they have multiple distinct conformations at the monomer level and higher association

2.1 2.1 Simulations free of experimental data

Atomistic molecular dynamics (MD) simulations in explicit environment offer the most detailed picture of protein folding. The longest trajectory on the fastest computer (Anton) reached 1 ms for the globular ubiquitin protein [25]. This time is sufficient for sampling the monomeric state of amyloid proteins, but is clearly insufficient for capturing all association-dissociation events during the lag phase, each event taking place with a timescale of hundreds of ns and ms [26], [27]. In the past

3.1 3.1 Aβ in aqueous solution

The Aβ42 dimer was subject to atomistic REMD using OPLS-AA, CHARMM22*, AMBER99sb-ildn and AMBERsb14 for a total of 144 μs [74]. The configurations are predicted to be mainly turn/coil with the calculated cross-collision sections (CCSs), hydrodynamics radius, and SAXS profiles independent of the force field. However, the secondary, tertiary and quaternary conformations differ between the force fields. The α-helix content varies between 3 and 20%, and the population of the intramolecular

4 4 Conclusions

We have reviewed recent results of computer simulations aimed at determining the structure of the Aβ, tau, and α-synuclein protein in aqueous solution at different association steps. Significant progress has been made using more sophisticated force fields, atomistic and coarse-grained models coupled to much efficient sampling approaches and longer simulation times at the monomer level. We also have presented for the first time the application of the PEP-FOLD framework for the α-synuclein

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We acknowledge support by the “Initiative d’Excellence” program from the French State (Grant “DYNAMO”, ANR-11-LABX-0011-01, and “CACSICE”, ANR-11-EQPX-0008). PD thanks Université de Paris, CNRS and PSL.

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