The paper explores the relationship between protein folding and binding, suggesting that the folding process can enhance the binding kinetics of a protein to its target. The authors propose the "fly-casting mechanism," where a partially unfolded protein has a larger capture radius for the binding site compared to a fully folded state. This mechanism allows the protein to bind weakly at a distance and then fold as it approaches the target, increasing the binding rate. The study uses a free energy functional to model the binding process, considering both the protein's internal structure and its interaction with the target. The fly-casting mechanism is illustrated through a hypothetical example of a repressor molecule binding to DNA, showing that the binding rate can be significantly enhanced over that of a fully folded protein. The mechanism is particularly effective at low concentrations, which is relevant in gene regulation. The authors also discuss the implications of this mechanism for understanding the dynamics of protein binding and the potential for kinetic discrimination in biological systems.The paper explores the relationship between protein folding and binding, suggesting that the folding process can enhance the binding kinetics of a protein to its target. The authors propose the "fly-casting mechanism," where a partially unfolded protein has a larger capture radius for the binding site compared to a fully folded state. This mechanism allows the protein to bind weakly at a distance and then fold as it approaches the target, increasing the binding rate. The study uses a free energy functional to model the binding process, considering both the protein's internal structure and its interaction with the target. The fly-casting mechanism is illustrated through a hypothetical example of a repressor molecule binding to DNA, showing that the binding rate can be significantly enhanced over that of a fully folded protein. The mechanism is particularly effective at low concentrations, which is relevant in gene regulation. The authors also discuss the implications of this mechanism for understanding the dynamics of protein binding and the potential for kinetic discrimination in biological systems.