Before revision:  Unlike all previous proposals here we suggest, on a statistical thermodynamics basis, that the upper bound of the marginal stability of proteins also belongs to biomacromolecular complexes and its origin should be sought on fluctuations of the pairwise and many-body interactions on both the macro-molecules and the solvent. In other words, at the global minimum of the free energy all folding dominant forces are almost compensated in a state of quasi-equilibrium where the structures preserve their biological activity. Thus, mutations disrupting this equilibrium beyond the protein marginal stability upper bound ( 7.4 kcal/ mol) will be subject to negative selection and mutations that preserve it will be neutral or nearly neutral , with respect to the marginal stability.
After revision:  Unlike all previous proposals here we suggest, on a statistical thermodynamics basis, that the upper bound of the marginal stability of proteins ( 7.4 kcal/ mol) will be subject to negative selection and mutations that preserve it will be neutral or nearly neutral , with respect to the marginal stability.