title: Structure-based approach to the design of BakBH3 mimetic peptides with increased helical propensity.
abstract: The Bcl-2 family of proteins are well-characterized regulators of the intrinsic apoptotic pathway. Proteins within this family can be classified as either prosurvival or prodeath members and the balance between them present at the mitochondrial membrane is what determines if the cell lives or dies. Specific interactions among Bcl-2 family proteins play a crucial role in regulating programmed cell death. Structural studies have established a conserved interaction pattern among Bcl-2 family members. This interaction is mediated by the binding of the hydrophobic face of the amphipathic α-helical BH3 domain into a conserved hydrophobic groove on the prosurvival partners. It has been reported that an increase in the helical content of BH3 mimetic peptides considerably improves the binding affinity. In this context, this work states for designing peptides derived from the BH3 domain of the proapoptotic protein Bak by substitution of some non-interacting residues by the helical inducing residue Aib. Different synthetic peptides preserving BakBH3 relevant interactions were proposed and simulated presenting a better predicted binding energy and higher helical content than the wild type Bak peptide.
authors.affiliation: Department of Physical Chemistry, University of Barcelona (UB) and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, C/Martí i Franquès 1, 08028, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Delgado-Soler
authors.forename: Maria
authors.initials: M
authors.lastname: Del Mar Orzaez
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein; D013816:Thermodynamics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry*; D051020:bcl-X Protein / Q000737:chemistry
chemical_list: D010446:Peptide Fragments; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
references.citation: J Comput Chem. 2005 Dec;26(16):1668-88
references.pmid: 16200636
references.citation: J Biol Chem. 2011 Mar 18;286(11):9382-92
references.pmid: 21148306
references.citation: J Biomol Struct Dyn. 2013;31(1):65-77
references.pmid: 22803956
references.citation: Pharm Res. 2009 Jul;26(7):1547-60
references.pmid: 19407932
references.citation: Science. 1997 Feb 14;275(5302):983-6
references.pmid: 9020082
references.citation: J Comput Aided Mol Des. 2011 May;25(5):413-26
references.pmid: 21523491
references.citation: Mol Cell. 2010 Feb 12;37(3):299-310
references.pmid: 20159550
references.citation: J Comput Chem. 2002 Oct;23(13):1244-53
references.pmid: 12210150
references.citation: Curr Opin Cell Biol. 2009 Dec;21(6):871-7
references.pmid: 19822411
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: Biopolymers. 2000-2001;56(4):275-91
references.pmid: 11754341
references.citation: Acc Chem Res. 2000 Dec;33(12):889-97
references.pmid: 11123888
references.citation: Curr Opin Oncol. 2009 Nov;21(6):516-23
references.pmid: 19730103
references.citation: Proteins. 2008 Nov 1;73(2):492-514
references.pmid: 18452209
references.citation: Oncogene. 2011 Jan 6;30(1):1-20
references.pmid: 20935674
references.citation: Curr Mol Pharmacol. 2008 Nov;1(3):244-54
references.pmid: 20021437
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S2-19
references.pmid: 19641503
references.citation: Bioorg Med Chem Lett. 2005 Oct 15;15(20):4467-9
references.pmid: 16137879
references.citation: Bioorg Med Chem Lett. 2004 Mar 22;14(6):1403-6
references.pmid: 15006371
references.citation: Mol Cancer Ther. 2004 Nov;3(11):1343-54
references.pmid: 15542773
references.citation: Protein Sci. 2000 Dec;9(12):2528-34
references.pmid: 11206074
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(1):487-91
references.pmid: 2296604
references.citation: Biopolymers. 1992 Jan;32(1):61-71
references.pmid: 1617151
references.citation: Cancer Lett. 2011 Jan 28;300(2):105-14
references.pmid: 21036469
references.citation: J Mol Biol. 2008 Jul 25;380(5):958-71
references.pmid: 18589438
references.citation: J Mol Biol. 2010 May 21;398(5):747-62
references.pmid: 20363230
references.citation: Proteins. 2006 Nov 15;65(3):712-25
references.pmid: 16981200
references.citation: J Mol Biol. 2003 Jul 18;330(4):891-913
references.pmid: 12850155
references.citation: J Pept Sci. 2004 May;10(5):274-84
references.pmid: 15160839
references.citation: J Comput Chem. 2003 Dec;24(16):1999-2012
references.pmid: 14531054