title: Molecular dynamics simulation and automated docking of the pro-apoptotic Bax protein and its complex with a peptide designed from the Bax-binding domain of anti-apoptotic Ku70.
abstract: Bax, a multi-domain protein belonging to the large family of Bcl-2 proteins, has a pivotal role for the initiation of the cytochrome c-mediated apoptosis, a vital physiologic process to eliminate damaged or unwanted cells. In response to specific stimuli Bax translocates from cytosol to mitochondria outer membrane where a process of oligomerization occurs with pore formation through which cytochrome c and other death molecules escape. The pro-death action of Bax is regulated by the interaction with other pro-survival proteins. However, the conformational changes and the structural details necessary for homo and hetero interaction with other regulating proteins are largely unknown. This article reports a combined investigation of molecular dynamics (MD) simulation and automated docking that evidence the molecular regions of Bax involved in the binding with anti-apoptotic exapeptide (Bip) designed from Ku70, a subunit of the protein complex essential for non-homologous DNA repair but that inhibits also the Bax translocation to mitochondria. Since Bip suppresses apoptosis induced by several anti-cancer drugs, it appears relevant to achieve a better understanding of the structural and dynamical aspects that characterize the Bip-Bax complex in view of potential therapeutic implications. The present results show that the Bax region with the highest affinity for Bip is located in proximity of BH3 homology domain of Bax and also involves the alpha-helices 1 and 8. Moreover, the comparison of essential motions of Bax at 300 and 400 K before and after the formation of the complex with Bip evidences how the binding with the exa-peptide affects the collective motions of specific molecular districts of Bax considered to have functional relevance.
authors.affiliation: Department of Biochemistry and Biophysics, Seconda Università degli Studi di Napoli, 80138 Napoli, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mancinelli
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Ettore
authors.initials: E
authors.lastname: Bismuto
mesh_terms: D000595:Amino Acid Sequence; D034961:Antigens, Nuclear / Q000737:chemistry / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D000072200:Ku Autoantigen; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D051017:Apoptosis Regulatory Proteins; C474007:Bax protein (53-86); D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D000072200:Ku Autoantigen