The lower DG with LY3537982 is associated with an improved DH. This representative complex configuration of LY3537982 shows the Thr58 to exist in the "flipped" orientation, i.e., the oxygen of the threonine is not accessible to the conserved water. With LY3537982 additional high-energy hydration sites are observed next to Lys16 and P-loop (Figure ). ). The predicted energy barrier is above 35 kcal/mol, while the energetic barrier with the rotation from the other side is predicted to be extremely high (>100 kcal/mol). This suggests that the (slow) interconversion of the GDC-6036 atropisomers would take years . The predicted difference between the energy minima of GDC-6036 atropisomers is 0.34 kcal/mol.