Accurate prediction of the bound form of the Akt pleckstrin homology domain using normal mode analysis to explore structural flexibility.

Molecular docking is often performed with rigid receptors. This can be a serious limitation, since the receptor often differs between bound and unbound forms or between bound forms with different ligands. We recently developed a normal-mode based docking method and showed that it is possible to obtain reasonable estimates of the complexed form of the pleckstrin homology (PH) domain of Akt, starting with the free form of the receptor. With inositol (1,3,4,5)-tetrakisphosphate (IP4) as the ligand the docked results agree with the known high-resolution X-ray crystal structure of the IP4-Akt PH domain complex. We also tested our methods with PH4, SC66, and PIT-1, several recently designed PH domain inhibitors. The results are shown to be consistent with available experimental data and previous modeling studies. The method we described can be used for molecular docking analysis even when only an approximation of the experimental structure or model is known.