Molecular modeling of human BAD and its interaction with PKAc or PP1c

Abstract

To build up the structure of human BAD (Bcl-2 antagonist of cell death), subsequently combined with PKAc or PP1c (protein phosphatase 1), to investigate the interaction relationship between BAD and its kinase/PTPese at the molecular level. Additionally, it is concerned with the search for all optimal positions and orientations of a set of amino acid residues of BAD, while its binding sites include N-termini (Glu19, Ala27, and Ser34–Lys35), BH3-located helical domain (Arg98–Lys126), and C-termini (Trp154–Ser163 and Ser167–Gln168). The related sites of PKAc are mainly assembled in C-terminal α/β-domain of PKAc, which comprises the KTL motif (47–49), Glu203 residue, a helical region (Asp241–Arg256), and the span from 328 to 333; while the interaction sites with BAD converge at C-terminal β-domain of PP1c, which includes the DEK motif (166–168), the stretch from 179 to 197 including a helix (Glu184–Arg188), Glu230–Asp242 segment containing Val232–His237 helix, and Glu287–Leu289 loop. In conclusion, analysis of the complex between BAD and PKAc or PP1c provides a novel viewpoint on the structural origins of molecular recognition. And the complex models suggest that BH3 domain of BAD interact with PKAc or PP1c by electrostatic, van der Waals contacts, hydrogen bond and salt bridge. This is helpful for our development and research of some new drugs, especially mimetic BH3 peptides and inspires scientists with BAD complex and molecular mechanism of its integrating glycolysis and apoptosis.