Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins

Santo, Kolattukudy P.; Berjanskii, Mark V.; Wishart, David S.; Stepanova, Maria

doi:10.4161/pri.5.3.16097

Cited by 21 publications

(46 citation statements)

References 84 publications

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“…The theory shows that such an image represents the degree of dynamic correlation (coupling) between the protein's atoms: points (images of atoms) that are located close to each other correspond to atoms whose motions are strongly correlated regardless of their proximity in secondary or tertiary structure of the protein, and more distant points correspond to a relatively independent motion [31], [33]. A suite of simple structural descriptors, such as the main chain flexibility and domains of correlated motion, have been derived within the ECD framework and successfully employed to analyze dynamics of proteins [32], [35], [47], [34]. It has been both proven theoretically [33] and confirmed by comparing numerical predictions with NMR experiments representing microsecond time regimes [31], [34].…”

Section: Methodsmentioning

confidence: 99%

“…Such domains can be identified through a simple nearest-neighbor clustering of the protein's image in the space of essential collective coordinates, as described in detail elsewhere [31], [32], [35], [34]. When employing the nearest-neighbor clustering technique to identify the dynamic domains, an interdomain distance must be selected which represents the minimum degree of correlation for two atoms to belong to the same domain.…”

Section: Methodsmentioning

confidence: 99%

“…Toward enabling robust interpretations, a novel essential collective dynamics (ECD) modeling framework has been recently introduced, which allows probing of persistent dynamic correlations in proteins based on short (a few hundreds of picoseconds) all-atom MD trajectories [31]–[35]. Relying on a statistical-mechanical theory, the ECD framework provides a transparent physical interpretation of the dimensionality reduction analyses in terms of a proteins' structural properties such as the main chain flexibility or dynamic domains of correlated motion, as well as allows for a reasonable match of the corresponding predictions with NMR-based measurements representing significantly longer time regimes than the MD trajectories used in the analysis.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms in the Activation of Abscisic Acid Receptor PYR1

et al. 2013

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The pyrabactin resistance 1 (PYR1)/PYR1-like (PYL)/regulatory component of abscisic acid (ABA) response (RCAR) proteins comprise a well characterized family of ABA receptors. Recent investigations have revealed two subsets of these receptors that, in the absence of ABA, either form inactive homodimers (PYR1 and PYLs 1–3) or mediate basal inhibition of downstream target type 2C protein phosphatases (PP2Cs; PYLs 4–10) respectively in vitro. Addition of ABA has been shown to release the apo-homodimers yielding ABA-bound monomeric holo-receptors that can interact with PP2Cs; highlighting a competitive-interaction process. Interaction selectivity has been shown to be mediated by subtle structural variations of primary sequence and ligand binding effects. Now, the dynamical contributions of ligand binding on interaction selectivity are investigated through extensive molecular dynamics (MD) simulations of apo and holo-PYR1 in monomeric and dimeric form as well as in complex with a PP2C, homology to ABA insensitive 1 (HAB1). Robust comparative interpretations were enabled by a novel essential collective dynamics approach. In agreement with recent experimental findings, our analysis indicates that ABA-bound PYR1 should efficiently bind to HAB1. However, both ABA-bound and ABA-extracted PYR1-HAB1 constructs have demonstrated notable similarities in their dynamics, suggesting that apo-PYR1 should also be able to make a substantial interaction with PP2Cs, albeit likely with slower complex formation kinetics. Further analysis indicates that both ABA-bound and ABA-free PYR1 in complex with HAB1 exhibit a higher intra-molecular structural stability and stronger inter-molecular dynamic correlations, in comparison with either holo- or apo-PYR1 dimers, supporting a model that includes apo-PYR1 in complex with HAB1. This possibility of a conditional functional apo-PYR1-PP2C complex was validated in vitro. These findings are generally consistent with the competitive-interaction model for PYR1 but highlight dynamical contributions of the PYR1 structure in mediating interaction selectivity suggesting added degrees of complexity in the regulation of the competitive-inhibition.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms in the Activation of Abscisic Acid Receptor PYR1

et al. 2013

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“…In this work, MD and FMD simulations were combined to study the thermostability and the dynamics of the bank vole prion protein (bvPrPc) and the turtle prion protein (tPrPc). TSE has not been observed in turtle, and turtle prion protein is concluded as one of the prion proteins of TSE resistant species [19,20]. The bank vole (Clethrionomys glareolus) has recently attracted interest due to unexpected features revealed by its use as a new laboratory animal for the study of prion diseases.…”

Section: Introductionmentioning

confidence: 99%

Dynamics study on the stability of animal prion proteins

Chen¹,

Duan²,

Zhu³

et al. 2014

Turk J Bioch

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“…Our aim is to monitor the evolution of new emerging secondary structures, particularly the formation b-sheet structures, and compare the stability of these structures, in several hypothetical aS constructs starting from their respective unfolded configurations. We also report our analysis of the resulting structures obtained via MD simulations using the novel essential collective dynamics (ECD) methodology [44][45][46][47][48][49][50][51][52][53].…”

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confidence: 99%

Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

Mane

Stepanova

2016

FEBS Open Bio

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Human α‐synuclein (αS) is an intrinsically disordered protein associated with Parkinson's disease. Molecular mechanisms of corruptive misfolding and aggregation of αS resulting in the disease, as well as the structure and other properties of the corresponding oligomers are not entirely understood yet, preventing the development of efficient therapies. In this study, we investigate the folding dynamics of initially unfolded hypothetical αS constructs in water using all‐atom molecular dynamics simulations. We also employ the novel essential collective dynamics method to analyze the results obtained from the simulations. Our comparative analysis of monomeric, dimeric, and tetrameric αS models reveals pronounced differences in their structure and stability, emphasizing the importance of small oligomers, particularly dimers, in the process of misfolding.

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Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins

Cited by 21 publications

References 84 publications

Molecular Mechanisms in the Activation of Abscisic Acid Receptor PYR1

Molecular Mechanisms in the Activation of Abscisic Acid Receptor PYR1

Dynamics study on the stability of animal prion proteins

Understanding the dynamics of monomeric, dimeric, and tetrameric α‐synuclein structures in water

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