Quantum mechanics

Receptor–ligand kinetics

Engineering

Chemical physics

Biology

Receptor

Folding (DSP implementation)

Biochemistry

Protein folding

Plasma protein binding

Thermodynamics

Physics

Diffusion

Binding site

Static electricity

Crystallography

Chemistry

Intrinsically disordered proteins

Biophysics

Electrical engineering

Nature Communications

Intrinsically disordered proteins (IDPs) usually fold during binding to target proteins. In contrast to interactions between folded proteins, this additional folding step makes the binding process more complex. Understanding the mechanism of coupled binding and folding of IDPs requires analysis of binding pathways that involve formation of the transient complex (TC). However, experimental characterization of TC is challenging because it only appears for a very brief period during binding. Here, we use single-molecule fluorescence spectroscopy to investigate the mechanism of diffusion-limited association of an IDP. A large enhancement of the association rate is observed due to the stabilization of TC by non-native electrostatic interactions. Moreover, photon-by-photon analysis reveals that the lifetime of TC for IDP binding is at least two orders of magnitude longer than that for binding of two folded proteins. This result suggests the long lifetime of TC is generally required for folding of IDPs during binding processes.

Diffusion-limited association of disordered protein by non-native electrostatic interactions