title: Probabilistic Determination of Native State Ensembles of Proteins.
abstract: The motions of biological macromolecules are tightly coupled to their functions. However, while the study of fast motions has become increasingly feasible in recent years, the study of slower, biologically important motions remains difficult. Here, we present a method to construct native state ensembles of proteins by the combination of physical force fields and experimental data through modern statistical methodology. As an example, we use NMR residual dipolar couplings to determine a native state ensemble of the extensively studied third immunoglobulin binding domain of protein G (GB3). The ensemble accurately describes both local and nonlocal backbone fluctuations as judged by its reproduction of complementary experimental data. While it is difficult to assess precise time-scales of the observed motions, our results suggest that it is possible to construct realistic conformational ensembles of biomolecules very efficiently. The approach may allow for a dramatic reduction in the computational as well as experimental resources needed to obtain accurate conformational ensembles of biological macromolecules in a statistically sound manner.
authors.affiliation: Bioinformatics Centre, Department of Biology, Faculty of Science, University of Copenhagen , Copenhagen, Denmark.|Institute for Research in Biomedicine , CH-6500 Bellinzona, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Olsson
authors.affiliation: Laboratory of Physical Chemistry, Eidgenössische Technische Hochschule Zürich , 8093 Zürich, Switzerland.
authors.forename: Beat Rolf
authors.initials: BR
authors.lastname: Vögeli
authors.affiliation: Institute for Research in Biomedicine , CH-6500 Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, Faculty of Science, University of Copenhagen , Copenhagen, Denmark.
authors.forename: Wouter
authors.initials: W
authors.lastname: Boomsma
authors.affiliation: Cellular Signal Integration Group, Center for Biological Sequence Analysis, Technical University of Denmark , Lyngby, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Ferkinghoff-Borg
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, Faculty of Science, University of Copenhagen , Copenhagen, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.affiliation: Bioinformatics Centre, Department of Biology, Faculty of Science, University of Copenhagen , Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hamelryck