Intrinsically disordered linkers provide multi-domain proteins with degrees of conformational freedom that are often essential for function. These highly dynamic assemblies represent a significant fraction of all proteomes, and deciphering the physical basis of their interactions represents a considerable challenge. Here we describe the difficulties associated with mapping the large-scale domain dynamics and describe two recent examples where solution state methods, in particular NMR spectroscopy, are used to investigate conformational exchange on very different timescales.
Keywords: chemical exchange saturation transfer (CEST); conformational dynamics; free-energy landscape; multi-domain proteins; nuclear magnetic resonance (NMR); single molecule Förster resonance energy transfer (FRET); small angle scattering.