Computational studies of chemical reactions in complex environments such as proteins, nanostructures, or on surfaces require accurate and efficient atomistic models applicable to the nanometer scale. In general, an accurate parametrization of the atomistic entities will not be available for arbitrary system classes, but demands a fast automated system-focused parametrization procedure to be quickly applicable, reliable, flexible, and reproducible. Here, we develop and combine an automatically parametrizable quantum chemically derived molecular mechanics model with machine-learned corrections under autonomous uncertainty quantification and refinement. Our approach first generates an accurate, physically motivated model from a minimum energy structure and its corresponding Hessian matrix by a partial Hessian fitting procedure of the force constants. This model is then the starting point to generate a large number of configurations for which additional off-minimum reference data can be evaluated on the fly. A ∆-machine learning model is trained on these data to provide a correction to energies and forces including uncertainty estimates. During the procedure, the flexibility of the machine learning model is tailored to the amount of available training data. The parametrization of large systems is enabled by a fragmentation approach. Due to their modular nature, all model construction steps allow for model improvement in a rolling fashion. Our approach may also be employed for the generation of system-focused electrostatic molecular mechanics embedding environments in a quantum mechanical molecular-mechanical hybrid model for arbitrary atomistic structures at the nanoscale.

We present a protocol for the fully automated construction of quantum mechanical (QM)−classical hybrid models by extending our previously reported approach on selfparametrizing system-focused atomistic models (SFAMs)

Rieske dioxygenases belong to the non-heme iron family of oxygenases and catalyze important cis-dihydroxylation as well as O-/N-dealkylation and oxidative cyclization reactions for a wide range of substrates. The lack of substrate coordination at the non-heme ferrous iron center, however, makes it particularly challenging to delineate the role of the substrate for productive O 2 activation. Here, we studied the role of the substrate in the key elementary reaction leading to O 2 activation from a theoretical perspective by systematically considering (i) the 6-coordinate to 5-coordinate conversion of the non-heme Fe II upon abstraction of a water ligand, (ii) binding of O 2 , and (iii) transfer of an electron from the Rieske cluster. We systematically evaluated the spin-state-dependent reaction energies and structural effects at the active site for all combinations of the three elementary processes in the presence and absence of substrate using naphthalene dioxygenase as a prototypical Rieske dioxygenase. We find that reaction energies for the generation of a coordination vacancy at the non-heme Fe II center through thermoneutral H 2 O reorientation and exothermic O 2 binding prior to Rieske cluster oxidation are largely insensitive to the presence of naphthalene and do not lead to formation of any of the known reactive Fe-oxygen species. By contrast, the role of the substrate becomes evident after Rieske cluster oxidation and exclusively for the 6-coordinate non-heme Fe II sites in that the additional electron is found at the substrate instead of at the iron and oxygen atoms. Our results imply an allosteric control of the substrate on Rieske dioxygenase reactivity to happen prior to changes at the non-heme Fe II in agreement with a strategy that avoids unproductive O 2 activation.[a] K.

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