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These data are consistent with the hypothesis that shorter PEG chains can act as stiff, rigid units where the extended conformation closely resembles the average end-to-end distance. Indeed, our MD simulations qualitatively reproduce these results, demonstrating that shorter PEG chains (JQ1 quenching occurs when the PEG chain flexibility allows for increased probability of direct contacts to form. However, with longer PEG chains, chain entropy favors a loose configuration, decreasing the contact probability Thus, at a qualitative level, it is appropriate to correlate the PEG length at which the fluorescence intensity reaches a minimum with the distance that separates the tethering points of the fluorophore and the PEG chain. However, the interaction between the PEG chain and other components in the system is critical. Therefore, it is conceivable that the interaction between the PEG chain and the environment can affect the observed behavior. Given the structural similarity between VGICs and the Epacadostat available chemical anchors, the strategy established here can be extended to examine more-complex proteins such as the heteromultimeric voltage-gated Na+ or Ca+ channels. As such, this method can be used to complement chemical and spectroscopic approaches based on the target, desired LY294002 manufacturer readout, and system constrains. Furthermore, with the recent progress of unnatural amino acid (UAA) incorporation in chemical biology, one can easily adapt a tethered quencher strategy to investigate protein-protein interactions and estimate distances without the limitations of the fluorophore attachments. Such an application may utilize a combination of chemistry, pharmacology, and toxicology, and fluorescence spectroscopy in addition to UAA incorporation. For example, PEG units can be added to a target molecule (48?and?49), Click chemistry can be used to attach an array of bioconjugates, and fluorescent UAA derivatives (with turn-on, turn-off properties) can be incorporated into the protein backbone along with target-selective toxins in a site-specific manner (2?and?50). It is also notable that the fundamental characteristics of the tethered quencher probes can be tailored based on the biological system using caged groups or profluorescent derivatives, various quenching molecules, and anchoring pairs. For example, we successfully substituted the nitroxy radical for a brominated moiety and consistently achieved quenching (?70% relative to NO?) of our fluorescent probe. The flexibility afforded by our approach allows one to develop a strategy suitable for not only their protein of interest but within the expression system.