Abstract
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.
Highlights
In 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
To demonstrate the capabilities of the CoNSEnsX method and the features of dynamic structural ensembles, we present a detailed analysis of different ensembles of three proteins: human ubiquitin as a well-characterized and relatively rigid protein, a 35-residue protease inhibitor as a small flexible protein and a disordered protein
The CoNSEnsX web server In protein nuclear magnetic resonance (NMR), the widely used structure calculation protocols, termed single conformer refinement (SCR) methods below, yield a family of conformers, each and every one aimed at corresponding to a set of experimental restraints as much as possible
Summary
In 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. Dynamical studies of the past decade led to the emerging paradigm that the so-called ‘native structure’ of a protein can be better viewed as a number of more or less similar conformers interconverting on different time scales. Functional interactions perturb this state by shifting the equilibrium towards ‘active conformations’ that are present but are low-populated in the apo state. Accuracy can only be reliably assessed by means of independent measurements which can range from obtaining distinct parameter sets not used for structure calculations (cross-validation) to the reproduction of the full structure determination procedure by a different research group
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