Single-molecule dynamics reveals cooperative binding-folding in protein recognition

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Understanding biomolecular interactions is crucial for deciphering molecular function and recognition.
• Traditionally, molecular structure has been considered the primary determinant of function.
• The role of flexibility in biomolecular recognition requires further investigation.

Purpose of the Study:

• To investigate the role of molecular flexibility in biomolecular recognition.
• To combine single-molecule experiments with computational modeling to explore binding mechanisms.
• To elucidate the interplay between binding and folding in protein-protein interactions.

Main Methods:

• Employed a coarse-grained molecular dynamics model (Go model) on the residue level.
• Biased the energy function towards the native binding structure to explore the free-energy landscape.
• Utilized single-molecule experiments to observe dynamic fluctuations in conformational states.

Main Results:

• Identified two distinct conformational states at the free-energy minimum: partially folded with significant binding, and natively folded with native binding.
• Demonstrated that binding precedes complete folding, with subsequent coupled binding and folding to reach the native state.
• Experimental findings of dynamic fluctuations quantitatively matched theoretical predictions of binding-associated conformational changes.

Conclusions:

• Biomolecular recognition is governed by both structure and flexibility.
• Binding and folding are coupled processes in achieving native protein-protein interactions.
• The study provides fundamental insights into biomolecular recognition mechanisms, aiding in the design of new interactions.