I942 was shown to be a partial activator of EPAC1, and proposed to stabilize an intermediate conformation, that lies between known active and inactive EPAC1 14 states. Application of our sMD/MSM protocol shows that EPAC1 in complex with I942 occupies the active state with 5% (IQR 1-23%) probability, and the intermediate state with 56% (IQR 49-59%) probability (Figure5). The small increase in active state probability over EPAC1 alone is consistent with the partial activation of EPAC1 by I942 observed experimentally. Likewise there is also an increase in the intermediate state probability compared to the ca. 40% observed with apo EPAC1. Shao et al.'s NMR study suggested that EPAC1-I942 populates the active state with a ca. 30% probability. The lower values observed here may be due to inaccuracies in the molecular model or a different partitioning of EPAC1's conformational space into active/intermediate/inactive states between MD and NMR methodologies.