Is stoichiometry-driven protein folding getting out of thermodynamic control?

The views on protein folding have evolved from simple force-driven folding (3), i.e., the sum of many different small interactions (such as van der Waals interactions, hydrophobic interactions, hydrogen bonds, electrostatic interactions and ion pairs), to complex, free energy-driven “folding funnel” model (4) based on the energy landscape theory of protein folding (5). The latter is essentially a thermodynamically controlled process and emphasizes that folding is driven by complex balance of enthalpy and entropy leading to global free energy minimum for the protein-solvent system, rather than by simple optimization of inter-atomic forces only within the protein.