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Access to the article is free, however registration and sign-in are required. Researchers have now observed in real time how a single molecule of calmodulin refolds and how it binds to a ligand. Single-molecule experiments are providing an increasingly detailed picture of the function of biomolecules and their assemblies. By watching one molecule at a time, one can observe phenomena that would be lost in macroscopic measurements averaged over large numbers of molecules. Force spectroscopy is particularly well suited to probe changes in biomolecular conformation (1-4). Like other single-molecule methods (5), it monitors the distance between two sites in a macromolecule, but in addition, a variable pulling force is coupled to this distance. Because stability is roughly exponentially sensitive to applied force, conformational equilibria can be probed over a wide free-energy range. On page 633 of this issue, Junker et al. (1) report the use of atomic force microscopy (AFM) to explore the force-dependent kinetics of calmodulin folding and ligand binding. Calmodulin, a calcium ion (Ca2+)-sensing protein ubiquitous in eukaryotes, contains two Ca2+-binding domains connected by a flexible linker. Upon Ca2+ binding, the domains open and partially expose their hydrophobic interior. This conformational change enables binding to various targets involved in biological processes ranging from apoptosis to muscle contraction (6).
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