Dynamic personalities of proteins

Abstract

Life is marked by change over time, and biologists explore this phenomenon by watching, for example, Caenorhabditis elegans developing from embryos into adults, mice running in a cage, and nerve cells firing. In search of how and why, biology arrived at the molecular level. Understanding protein function on an atomic level has been revolutionized by high-resolution X-ray crystallography, resulting in a surge in studies of structure-function relationships. The detail in these colourful structures flooding the covers of modern journals can be deceptive, suggesting that one unique structure, the 'folded state' , is the final answer. Ironically, the dynamic nature of biology seems to have been forgotten at this microscopic level.Physicists, however, will object to a static picture: they see proteins as soft materials that sample a large ensemble of conformations around the average structure as a result of thermal energy. A complete description of proteins requires a multidimensional energy landscape that defines the relative probabilities of the conformational states (thermodynamics) and the energy barriers between them (kinetics). In biology, this concept has recently gained traction, leading to an extension of the structure-function paradigm to include dynamics. To understand proteins in action, the fourth dimension, time, must be added to the snapshots of proteins frozen in crystal structures. A major obstacle is that it is not possible to watch experimentally individual atoms moving within a protein. Instead, sophisticated biophysical methods are needed to measure the physical properties from which the dynamics can be inferred.In this review, we discuss how protein function is rooted in the energy landscape. The basic concepts and the biophysical methods are illustrated by several examples. To avoid past semantic confusion about the term protein dynamics, we define it as any time-dependent change in atomic coordinates. Protein dynamics thus includes both equilibrium fluctuations and non-equilibrium effects. The fluctuations observed at equilibrium seem to govern biological function in processes both near and far from equilibrium; therefore, we focus on these motions. Non-equilibrium effects are also called dynamical effects 1 (the source of confusion 2 ), and they have a minimal effect on the overall rates of biological processes 3,4 . Biological motors that convert chemical energy to mechanical energy 5,6 are not discussed here. The energy landscapeAlthough the idea of an energy landscape might be most familiar in the context of protein folding (for example, the folding funnel hypothesis) [7][8][9] , this concept had already been applied to folded proteins more than 30 years ago by Frauenfelder and co-workers . Subsequent studies on myoglobin led to the idea that substates are in thermal equilibrium and that both solvent 13-15 and ligands influence the landscape (Fig. 1a). At the glass transition temperature 10,12 , an increase in anharmonic dynamics occurs in proteins, and this is interpreted as the protein no...

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“…2), into the Nterminal region of BtuB (see Methods). The X-band EPR spectra from spin labels placed at positions [1][2][3][4][5] in BtuB are shown in Figure 3, along with the position of these sites in the BtuB meso structure. These spectra are similar to those published previously, 22 and are composed of two components resulting from populations of spin labels that have different dynamics.…”

“…Proteins do not assume one unique structure but sample a range of conformational states over a wide range of timescales 1,2 ; furthermore, protein dynamics underlies function and is a key to enzyme activity and allosteric regulation. [3][4][5] Dynamics also underlies protein-protein recognition, which is often mediated by conserved and highly dynamic or unstructured regions of proteins.…”

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“…Over the recent years, the view and understanding of the fundamental principles underlying allostery have been enriched and often utterly reshaped as techniques such as NMR spectroscopy has been offering insights complementary to those provided by static structures. [6][7][8][9][10][11] The early crystallographic work on allosteric systems helped to advance and establish a purely structural, ''mechanical'' view. 12 Nevertheless, because allostery is fundamentally thermodynamic in nature, long-range communication may be mediated not only by changes in the mean conformation (enthalpic contribution) but also by changes in the dynamic fluctuations about the mean conformation (entropic contribution).…”