Our sequential optimization approach, starting from CCR's optimized parameters (see Tables and in SI) and incorporating a modest data set of DHFR-specific data, proved to be highly efficient in developing accurate parameters for DHFR (presented in Tables and S6 in SI). This strategy significantly reduced the computational cost typically associated with system-specific parametrizations while maintaining an adequate accuracy. The success of this approach suggests that developing parameters for mechanistically similar reactions can be achieved through strategic use of existing optimized parameters combined with targeted additional training data. As we will show below, the new parameters obtained with the extended data set are expected to be adequate to reproduce correctly both hydride transfer reactions in CCR and DHFR. the PMF profiles using umbrella sampling (see Figures and). Our approach involved a multi-step process to assess the accuracy and reliability of our optimized parameters against reference calculations at higher levels of theory.