1 Department of Systems Biology, Technical University of Denmark2 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3 Cellular Signal Integration, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4 University of Copenhagen5 Swiss Federal Institute of Technology6 Institute for Research in Biomedicine7 Department of Electrical Engineering, Technical University of Denmark8 Swiss Federal Institute of Technology
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.
Journal of Chemical Theory and Computation, 2014, Vol 10, Issue 8, p. 3484-3491