Probing Dynamic Protein Ensembles with Atomic Proximity Measures

Gáspári, Zoltán; Ángyán, Annamária F.; Dhir, Somdutta; Franklin, Dino; Perczel, András; Pintar, Alessandro; Pongor, Sándor

doi:10.2174/138920310794109201

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…In a typical NMR experiments, the simultaneous detection of signals from several "reporters" (NMR active nuclei) within a protein is possible, providing a comprehensive and detailed description of internal motions at atomic level, over a wide range of timescales. The great advantage of NMR spectroscopy is the ability of coupling the structure determination of polypeptide chains in solution with the description of their internal dynamics, over a wide range of timescales, ranging from picoseconds to several hours, mainly by the mean of spin relaxation and residual dipolar couplings measurements, as well as slow exchange motions [121][122][123][124].…”

Section: Experimental Techniquesmentioning

confidence: 99%

Molecular Determinants of Enzyme Cold Adaptation: Comparative Structural and Computational Studies of Cold- and Warm-Adapted Enzymes

Papaleo

Tiberti²,

Invernizzi³

et al. 2011

CPPS

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The identification of molecular mechanisms underlying enzyme cold adaptation is a hot-topic both for fundamental research and industrial applications. In the present contribution, we review the last decades of structural computational investigations on cold-adapted enzymes in comparison to their warm-adapted counterparts. Comparative sequence and structural studies allow the definition of a multitude of adaptation strategies. Different enzymes carried out diverse mechanisms to adapt to low temperatures, so that a general theory for enzyme cold adaptation cannot be formulated. However, some common features can be traced in dynamic and flexibility properties of these enzymes, as well as in their intra- and inter-molecular interaction networks. Interestingly, the current data suggest that a family-centered point of view is necessary in the comparative analyses of cold- and warm-adapted enzymes. In fact, enzymes belonging to the same family or superfamily, thus sharing at least the three-dimensional fold and common features of the functional sites, have evolved similar structural and dynamic patterns to overcome the detrimental effects of low temperatures.

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Section: Experimental Techniquesmentioning

confidence: 99%

Molecular Determinants of Enzyme Cold Adaptation: Comparative Structural and Computational Studies of Cold- and Warm-Adapted Enzymes

Papaleo

Tiberti²,

Invernizzi³

et al. 2011

CPPS

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“…Currently, there is no consensus on the evaluation of such conformer sets [ 13 ] and it is not straightforward to coin a generally acceptable method. In these cases, individual conformers might yield substantially different results in single-conformer evaluation and structure analysis tools [ 49 ], which are clearly not suitable to offer an overall picture of the ensemble. Moreover, there are some data types, notably S 2 order parameters that can only be interpreted as an ensemble property.…”

Section: Discussionmentioning

confidence: 99%

“…As protein ensembles reflecting dynamics are substantially diverse [ 49 ], the often cumbersome task of selecting a representative conformer becomes even more difficult. It is generally expected that the selected conformer conforms to most experimental data and is in some sense an 'average structure' of the molecule.…”

Section: Discussionmentioning

confidence: 99%

CoNSEnsX: an ensemble view of protein structures and NMR-derived experimental data

et al. 2010

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BackgroundIn conjunction with the recognition of the functional role of internal dynamics of proteins at various timescales, there is an emerging use of dynamic structural ensembles instead of individual conformers. These ensembles are usually substantially more diverse than conventional NMR ensembles and eliminate the expectation that a single conformer should fulfill all NMR parameters originating from 1016 - 1017 molecules in the sample tube. Thus, the accuracy of dynamic conformational ensembles should be evaluated differently to that of single conformers.ResultsWe constructed the web application CoNSEnsX (Consistency of NMR-derived Structural Ensembles with eXperimental data) allowing fast, simple and convenient assessment of the correspondence of the ensemble as a whole with diverse independent NMR parameters available. We have chosen different ensembles of three proteins, human ubiquitin, a small protease inhibitor and a disordered subunit of cGMP phosphodiesterase 5/6 for detailed evaluation and demonstration of the capabilities of the CoNSEnsX approach.ConclusionsOur results present a new conceptual method for the evaluation of dynamic conformational ensembles resulting from NMR structure determination. The designed CoNSEnsX approach gives a complete evaluation of these ensembles and is freely available as a web service at http://consensx.chem.elte.hu.

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“…Together with other key publications, we have previously shown the essential role of water with respect to structure, dynamics and activity of proteins (1)(2)(3)(4)(5), termed dynamics-structure-activity relationships (DSARs) (6), a key feature of water now extended to amyloid-β(Aβ) fibril proteins (7)(8)(9)(10)(11). It is well known, that the accumulation of the Aβ peptide in the brain is responsible for debilitating diseases, as in Alzheimer's and Parkinson's diseases (12).…”

Section: Introductionmentioning

confidence: 87%

The impact of water on the ambivalent behavior and paradoxical phenomenon of the amyloid-β fibril protein

Vajda

Perczel

2017

Biomolecular Concepts

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Abstract:The crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water's thermodynamic and kinetic solvation effects. As regards the water's character, its hindered-rotation barriers are also considered. The following protein molecules considered here are: the Aβ 40 (PDB ID: 2LMN), Aβ 42 (PDB ID: 5KK3 and 2NAO) and the double-layered Aβ 17−42 fibril. We discuss: (i) extracellular Aβ 40 and Aβ 42 fibril monomers exhibit an ambivalent propensity to transform into a helical form toward the N-term region and a β-strand-like form near the C-terminal; (ii) interfacial water molecules play a crucial role in protein-protein interactions, as molecular dynamics simulations have shown a significant impact on the protein-protein binding; (iii) it is shown that the spontaneous dimerization process of the Aβ 42 fibril protein in water occurs via a two-step nucleation-accommodation mechanism; (iv) MD simulations of the double-layered Aβ 17−42 fibril model show that the C ↔ C interface appears more energetically favorable than the N ↔ N interface due to large hydrophobic contacts; (v) the water's role in the HET-s prion and in the Aβ fibrillar aggregates; (vi) it was found that the monomer-oligomer equilibrium spontaneously dissociates into stable monomeric species when they are incubated up to 3 μm for a longer time (>1 week) in a physiological buffer.

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Probing Dynamic Protein Ensembles with Atomic Proximity Measures

Cited by 7 publications

References 32 publications

Molecular Determinants of Enzyme Cold Adaptation: Comparative Structural and Computational Studies of Cold- and Warm-Adapted Enzymes

Molecular Determinants of Enzyme Cold Adaptation: Comparative Structural and Computational Studies of Cold- and Warm-Adapted Enzymes

CoNSEnsX: an ensemble view of protein structures and NMR-derived experimental data

The impact of water on the ambivalent behavior and paradoxical phenomenon of the amyloid-β fibril protein

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