Simultaneous determination of protein structure and dynamics

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. Proteins on the move The dynamical properties of proteins are crucial to their function, yet dynamics are often considered separately from protein structure. A new method for determining structure combines NMR spectroscopy and molecular dynamics simulation to reveal the series of interconvertible conformations that constitute the native state of a protein in the cell. Application of this method to human ubiquitin shows that conventional structure determination severely underestimates the variability associated with the native state. In particular, the side chains of the protein are highly mobile, even in the hydrophobic core, whereas the backbone atoms display a more limited range of movement.