NDLI: Anti-apoptotic $Bcl-X_{L}$ protein in complex with BH3 peptides of pro-apoptotic Bak, Bad, and Bim proteins: Comparative molecular dynamics simulations

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Anti-apoptotic $Bcl-X_{L}$ protein in complex with BH3 peptides of pro-apoptotic Bak, Bad, and Bim proteins: Comparative molecular dynamics simulations

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lama, Dilraj Sankararamakrishnan, Ramasubbu
Description	Country affiliation: India Author Affiliation: Lama D ( Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.)
Abstract	The Bcl-2 family of proteins plays a central role in the regulation of mitochondrial outer-membrane permeabilization, a critical step in apoptosis. Heterodimerization between the pro- and anti-apoptotic members of Bcl-2 family is a key event in this process. Anti-apoptotic proteins have high levels of expression in many cancers and they have different affinities for different pro-apoptotic proteins. Experimentally determined structures of all members of Bcl-2 proteins have remarkably similar helical fold despite poor amino acid sequence identity. Peptides representing BH3 region of pro-apoptotic proteins have been shown to bind the hydrophobic cleft of anti-apoptotic proteins and this segment is responsible in modulating the apoptotic pathways in living cells. Understanding the molecular basis of protein–protein recognition is required to develop inhibitors specific to a particular anti-apoptotic protein. We have carried out molecular dynamics simulations on the anti-apoptotic $Bcl-X_{L}$ protein in complex with three different BH3 peptides derived from pro-apoptotic Bak, Bad and Bim proteins. Each complex structure was simulated for a period of 50 ns after 2.5 ns equilibration. Analysis of the simulation results showed that in the $Bcl-X_{L}$ protein, the helix containing the BH3 region is more flexible than other helices in all three simulations. A network of strong hydrophobic interactions exists between four of the six helices and they contribute significantly to the stability of this helix bundle protein. Analysis of $Bcl-X_{L}-BH3$ peptide interactions reveals the role of loop residues in the protein–peptide interactions in all three simulations. Bad and Bim peptides maintain strong hydrophobic and hydrophilic interactions with the helix preceding the central hydrophobic helix. Residues from this helix interact with an Arg residue in Bad and Bim peptides. This Arg residue is next to the conserved Leu residue and is replaced by Ala in Bak. Absence of these interactions and the helix propensity are likely to be the cause for Bak peptide's weaker binding affinity with the $Bcl-X_{L}$ protein. The results of this study have implications in the design of $Bcl-X_{L}-specific$ inhibitors. Proteins 2008. © 2008 Wiley-Liss, Inc.
File Format	HTM / HTML
ISSN	08873585
Issue Number	2
Volume Number	73
e-ISSN	10970134
Journal	Proteins: Structure, Function, and Bioinformatics
Language	English
Publisher	Wiley-Liss
Publisher Date	2008-11-01
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Amino Acid Sequence Bcl-2 Homologous Antagonist-killer Protein Research Support, Non-u.s. Gov't Peptide Fragments Comparative Study Humans Proto-oncogene Proteins Discipline Biochemistry Molecular Sequence Data Bcl-associated Death Protein Protein Interaction Domains And Motifs Journal Article Membrane Proteins Chemistry Apoptosis Regulatory Proteins Computer Simulation Proto-oncogene Proteins C-bcl-2 Bcl-x Protein
Content Type	Text
Resource Type	Article
Subject	Structural Biology Biochemistry Molecular Biology

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