Article

Nature 433, 128-132 (13 January 2005) | doi:10.1038/nature03199; Received 16 September 2004; Accepted 28 October 2004

Simultaneous determination of protein structure and dynamics

Kresten Lindorff-Larsen1,3,4, Robert B. Best1,3,4, Mark A. DePristo2,3, Christopher M. Dobson1 & Michele Vendruscolo1

  1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
  2. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
  3. Present addresses: Department of Protein Chemistry, Institute of Molecular Biology, University of Copenhagen, Øster Farimagsgade 2A, 4, DK-1353 Copenhagen K, Denmark (K.L.-L.); Laboratory of Chemical Physics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0520, USA (R.B.B.); Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA (M.A.D.)
  4. These authors contributed equally to this work

Correspondence to: Christopher M. Dobson1Michele Vendruscolo1 Correspondence and requests for materials should be addressed to M.V. (Email: mv245@cam.ac.uk) or C.M.D. (Email: cmd44@cam.ac.uk).

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We present a protocol for the experimental determination of ensembles of protein conformations that represent simultaneously the native structure and its associated dynamics. The procedure combines the strengths of nuclear magnetic resonance spectroscopy—for obtaining experimental information at the atomic level about the structural and dynamical features of proteins—with the ability of molecular dynamics simulations to explore a wide range of protein conformations. We illustrate the method for human ubiquitin in solution and find that there is considerable conformational heterogeneity throughout the protein structure. The interior atoms of the protein are tightly packed in each individual conformation that contributes to the ensemble but their overall behaviour can be described as having a significant degree of liquid-like character. The protocol is completely general and should lead to significant advances in our ability to understand and utilize the structures of native proteins.