(a)
(b)
Figure 3: Folding free energy difference between mutants and native wild-type along the simulation trajectory and throughout the tetramer-unfolded monomer equilibrium. Panels (a) and (b) refer to FoldX and BMF results, respectively. In the case of tetramer (A), is the global stability free energy change of tetramers, i.e., the free energy required to fold the tetramers from their unfolded monomers. Subscripts and are, respectively, mutant (MT-TTR or 3M-TTR, with their simplified notations and 3) and wild-type (WT-TTR). (B) is the free energy necessary to form the dimers from tetramers (TD). ΔΔ (C) is the free energy involved in the dissociation of dimers into folded monomers (DM) and (D) is the free energy of unfolding of individual monomers (M ).