To portray the SBMOpenMM library's usage, we ran folding simulations for the monomeric structure of the FoxP1 DNA-binding domain. Figure shows five out of the fifteen folding/unfolding equilibrium replicas ran for this system, using an AA SBM at the folding temperature of the system (see Sections SI-III.C and SI-IV.A for details, including the rest of the replicas). The native contacts employed to define the SBM were calculated using the shadow contact algorithm. The code for running the simulations is identical to the one shown in the Implementation section above. The simulations show different numbers of folding/unfolding transitions, ranging from one to eight, indicating independence on the course of the phase space sampled among them (Figure and S1). We analyzed the simulated trajectories using the Markov-State Model (MSM) framework implemented in the PyEMMA package (for details on MSM construction and validation, see Section SI-IV.B). The system free energy was projected onto the two slowest time-lagged independent component analysis (TICA) dimensions (Figure ). The simulation reproduces the experimental folding mechanism of FoxP1 as a two-state folder. To follow the unfolding mechanism progression, we estimated the probability of contact formation at the folded, transition-state (TS), and unfolded regions (Figure ). While the folded configuration retains most of the native contacts, it shows diminished interactions for the contacts made by the N-and C-terminal residues (Figure , left matrix "b" triangle). Most native contacts are already lost at the TS; however, contacts made between strands 1, 2, and 3 hold the structure and are the last to be broken (Figure , right matrix "c" triangle).