Speeding molecular recognition by using the folding funnel: The fly-casting mechanism

Protein folding and binding are kindred processes, Many proteins in the cel l are unfolded, so folding and function are coupled. This paper investigate s how binding kinetics is influenced by the folding of a protein, We find t hat a relatively unstructured protein molecule can have a greater capture r adius for a specific binding site than the folded state with its restricted conformational freedom. In this scenario of binding, the unfolded state bi nds weakly at a relatively large distance followed by folding as the protei n approaches the binding site: the "fly-casting mechanism." We illustrate t his scenario with the hypothetical kinetics of binding a single repressor m olecule to a DNA site and find that the binding rate can be significantly e nhanced over the rate of binding of a fully folded protein.