Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamicsReport as inadecuate

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Biology Direct

, 12:2

Structural and Molecular Biology


BackgroundMolecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 SCA3 where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain JD, play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.

ResultsConformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate-open states was characterized by a rate constant higher than 700 ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.

ConclusionThis work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.

ReviewersThis article was reviewed by Oliviero Carugo, Bojan Zagrovic.

KeywordsAtaxin Replica exchange molecular dynamics Neurodegenerative Josephin Domain Protein plasticity Kinetics Thermodynamics AbbreviationsAt3Ataxin 3

JDJosephin Domain

MDMolecular dynamics

REMDReplica exchange molecular dynamics

RGRadius of gyration

Electronic supplementary materialThe online version of this article doi:10.1186-s13062-016-0173-y contains supplementary material, which is available to authorized users.

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Author: Gianvito Grasso - Jack A. Tuszynski - Umberto Morbiducci - Ginevra Licandro - Andrea Danani - Marco A. Deriu


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