ArticleBiology direct2017
Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics.
Article in Biology direct, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed.
- The Extent of Human Apolipoprotein A-I Lipidation Strongly Affects the β-Amyloid Efflux Across the Blood-Brain BarrierFrontiers in neuroscience · 2019Article
- Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol.International journal of molecular sciences · 2018Article
- Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.International journal of molecular sciences · 2018Article
- Destabilizing the AXH Tetramer by Mutations: Mechanisms and Potential Antiaggregation Strategies.Biophysical journal · 2018Article
- Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA.Molecules (Basel, Switzerland) · 2017Article
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Abstract
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. REVIEWERS: This article was reviewed by Oliviero Carugo, Bojan Zagrovic.
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