Docking study of bryostatins to protein kinase C delta Cys2 domain

The docking structure of bryostatin I, a potent activator of protein kinase C (PKC), to the crystal structure of PKC delta cys2 domain was examined co mputationally. Prior to the docking study, possible conformers of the 20-me mbered ring of bryostatin I were searched by the high-temperature molecular dynamics calculation method, For each conformer thus identified, the most stable docking model to PKC was searched without any presumptions, covering all possible binding modes and ligand conformations, using our automatic d ocking program ADAM, Among the seven conformers, the conformer with a ring conformation almost identical to that in the crystal (root mean square devi ation=0.187 Angstrom) yielded the most stable PKC-bryostatin I complex. The bryostatin molecule fits well to the cone-shaped bottom of the PKC binding cavity, forming four hydrogen bonds with main chain groups. On the basis o f this docking structure, the structure-activity relations of various bryos tatins are well explained.