title: Molecular dynamics study of segment peptides of Bax, Bim, and Mcl-1 BH3 domain of the apoptosis-regulating proteins bound to the anti-apoptotic Mcl-1 protein.
abstract: Mcl-1 has emerged as a potential therapeutic target in the treatment of several malignancies. Peptides representing BH3 region of pro-apoptotic proteins have been shown to bind the hydrophobic cleft of anti-apoptotic Mcl-1 and this segment is responsible for modulating the apoptotic pathways in living cells. Understanding the molecular basis of protein-peptide interaction is required to develop potent inhibitors specific for Mcl-1. Molecular dynamics simulations were performed for Mcl-1 in complex with three different BH3 peptides derived from Mcl-1, Bax, and Bim. Accordingly, the calculated binding free energies using MM-PBSA method are obtained and comparison with the experimentally determined binding free energies is made. The interactions involving two conserved charged residues (Aspi, and Arg/Lysi-4) and three upstream conserved hydrophobic residues (Leui-5, Ile/Vali-2, and Glyi-1, respectively) of BH3 peptides play the important roles in the structural stability of the complexes. The calculated results exhibit that the interactions of Bim BH3 peptides to Mcl-1 is stronger than the complex with Bax 19BH3 peptides. The hydrophobic residues (position i - 9, i - 8 and i + 2) of BH3 peptides can be involved in their inhibitory specificity. The calculated results can be used for designing more effective MCL-1 inhibitors.
authors.affiliation: a Institute of Applied Mathematics and Physics , Shanghai Dianji University , Shanghai 201306 , P.R. China.
authors.forename: Run-Ning
authors.initials: RN
authors.lastname: Zhao
authors.forename: Song
authors.initials: S
authors.lastname: Fan
authors.forename: Ju-Guang
authors.initials: JG
authors.lastname: Han
authors.forename: Guang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001667:Binding, Competitive; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein
keywords: Mcl-1 BH3 domain; anti-apoptotic Mcl-1 protein; apoptosis regulating proteins; free energy; hydrophobic residues; molecular dynamics simulation