Our modelling also support findings by Shao et al. on the partial activation of EPAC1 by I942. The presence of I942 increases the probabilities of both the active and intermediate states, compared to the apo EPAC1 model. In comparison with EPAC1-cAMP, only a slight movement towards an "in" conformation of the hinge is observed, and the PBC shift to the "in" conformation is incomplete. Since our EPAC1 models included the lid present in the catalytic region we could additionally investigate the effect of enforcing protein-ligand distance restraints between I942 and that region. The restraints to the lid region proved extremely effective in stabilizing the active conformation, yielding a model where the active state was almost exclusively populated (Figure ). In this restrained model, no ionic latch interactions were observed, indicating a complete exposure of the RAP binding site (Supplementary Figure ). Such active state stabilizing interactions have been observed in a X-Ray structure 11 of EPAC2-cAMP(Sp). The present simulations demonstrate that similar interactions occur with EPAC1. Since the EPAC1 construct used in the NMR work of Shao et al. did not include the lid region, 14 this role of the catayltic region in EPAC1 activation could not be evaluated. Consequently efforts to develop I942 derivatives into full EPAC1 agonists have so far focused on engagement of the PBC. Here use of a full-length EPAC1 model revealed an additional design strategy that features simultaneous engagement of the PBC and lid regions m( (Figure ). Having validated the sMD/MSM approach applied here with cAMP, L273W mutant and I942, further applications of the sMD/MSM methodology can be pursued to guide the design of I942 derivatives.