Fig. 3: Reaction paths of the esterification in insulin.

A Box plots for the spread of relative electronic energies of the stationary points of the reaction for the core model (n = 17), the 'quantum mechanical/molecular mechanical (QM/MM) stationary points' of the transplanted core model into the full structure with environment relaxation (n = 17), 'QM/MM IRC' obtained from an intrinsic reaction coordinate (IRC) scan starting from the transition state in the full QM/MM model (n = 16), and 'QM/MM exploration' calculated in a single-ended reaction search in the full structural model starting from the reactive complex of the reactants (n = 9). The energies were calculated with PBE-D3(def2-SVP)/SFAM single-point calculations on DFTB3/SFAM structures (SFAM: system-focused atomistic models), and are given relative to the lowest reactant conformer energy of the core model and of the single-ended QM/MM strategy for the three QM/MM strategies. The whiskers of the boxes show the minimum and maximum values, the boxes depict the second and third quartile, and the line in the box denotes the median of the energy values. The horizontal bar annotates the elementary step with the lowest reactant energy in the core model, and the respective elementary step in the QM/MM model for which the core model step served as an input. The activation and reaction energies for this elementary step in all approaches are annotated with vertical arrows (for details and energy decomposition analyses, see Table 8 in the SI). B Stationary points of one of the DFTB3/SFAM minimum energy reaction paths; the QM region is shown in ball-and-stick representation, whereas the MM region is presented in a stick-cartoon representation. Hydrogen atoms are omitted in the MM region for the sake of clarity. Source data of panel (A) are provided as a Source Data file.