J Am Chem Soc. 2009 Dec 30;131(51):18314-26.

Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements.

Allison JR, Varnai P, Dobson CM, Vendruscolo M.

Source

Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.

Abstract

Natively unfolded proteins present a challenge for structure determination because they populate highly heterogeneous ensembles of conformations. A useful source of structural information about these states is provided by paramagnetic relaxation enhancement measurements by nuclear magnetic resonance spectroscopy, from which long-range interatomic distances can be estimated. Here we describe a method for using such distances as restraints in molecular dynamics simulations to obtain a mapping of the free energy landscapes of natively unfolded proteins. We demonstrate the method in the case of alpha-synuclein and validate the results by a comparison with electron transfer measurements. Our findings indicate that our procedure provides an accurate estimate of the relative statistical weights of the different conformations populated by alpha-synuclein in its natively unfolded state.

PMID:: 20028147; [PubMed - indexed for MEDLINE]

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Wellcome Trust/United Kingdom

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