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