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Many biological macromolecular interactions proceed via lowly-populated, highly transient species that arise from rare excursions between the minimum free energy configuration and other local minima of the free energy landscape. Little is known about the structural properties of such lowly-occupied states since they are difficult to trap and hence inaccessible to conventional structural and biophysical techniques. Yet these states play a crucial role in a variety of dynamical processes including molecular recognition and binding, allostery, induced-fit and self-assembly. Here we highlight recent progress in paramagnetic nuclear magnetic resonance to detect, visualize and characterize lowly-populated transient species at equilibrium. The underlying principle involves the application of paramagnetic relaxation enhancement (PRE) in the fast exchange regime. Under these conditions the footprint of the minor species can be observed in the PRE profiles measured for the major species, providing distances between the paramagnetic label and protons of interest are shorter in the minor species than the major one. Ensemble simulated annealing refinement directly against the PRE data permits one to obtain structural data on the minor species. We have used the PRE (a) to detect and characterize the stochastic target search process whereby a sequence-specific transcription factor (the Hox-D9 homeodomain) binds to non-cognate DNA sites as a means of enhancing the rate of specific association via intramolecular sliding and intermolecular translocation; (b) to directly visualize the distribution of non-specific transient encounter complexes involved in the formation of stereospecific protein-protein complexes; (c) to detect and visualize ultra-weak self-association of a protein, a process that is relevant to early nucleation events involved in the formation of higher order structures; and (d) to determine the structure of a minor species for a multidomain protein (maltose binding protein) where large interdomain motions are associated with ligand binding, thereby shedding direct light on the fundamental question of allostery versus induced fit in this system. The PRE offers unique opportunities to directly probe and explore in structural terms lowly-populated regions of the free energy landscape and promises to yield fundamental new insights into biophysical processes.

Visualizing lowly-populated regions of the free energy landscape of macromolecular complexes by paramagnetic relaxation enhancement