Fig. 6: Changing the bound ligand in p38α MAPK–2 to 1 disrupts the stability of the kinase.
From: Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors
a Salt bridge profile of Lys53 with 1 in 2-S3 is shifted towards the profile which is observed for p38α MAPK-1. Salt bridge interactions observed in simulations of 2 are shown in parenthesis and the differences are indicated with blue arrows. Solvent exposure of the salt bridge forming residues Glu71 (b) and Asp168 (c). Solvent exposure of the hydrophobic residues Val38 (d), Leu74 (e), Leu75 (f), and Phe169 (g). In b-g the blue background indicates solvent exposure (where ≥1 water molecule is located within 3 Å of the side chain) and the yellow background indicates when the side chain is not exposed to solvent. h Interactions for 1 when bound in 2-S3 conformation. The inhibitor loses its key water mediated interactions to Phe169 and interactions to Asp168 are diminished. In parenthesis are the interaction frequencies observed for 1 in its preferred p38α MAPK binding conformation (Fig. 1d). Simulation data was analysed for each 1 ns i.e. data in a–d consist of 90,120 and 86,505 individual data points for 1 in 2-S3 and 2, respectively. Source data are provided as a Source Data file.
