Fig. 4. The effect of T106 rotamer states of the p38α kinase on the calculated ligand binding ΔG. Free energy surfaces (A) of the χ₁ dihedral angle for the T106 residue obtained from well tempered metadynamics simulations starting from 3fly and 1wfc structures as well as from the output of 1 μs equilibrations started from 3fly. χ₁ dihedral angle for the T106 residue in the crystallographic apo (1wfc) and holo (3fly) states, as well as in 5 independent simulations of 1 μs each (B). Binding ΔG calculated by initializing apo state simulations with the 1wfc structure (C) and the end-states from 1 μs simulations (D). Dark and light shaded areas represent regions deviating from experiment by at most 1 and 2 kcal mol⁻¹.