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- W3045576747 endingPage "1114" @default.
- W3045576747 startingPage "1114" @default.
- W3045576747 abstract "Mcl1 is a primary member of the Bcl–2 family—anti–apoptotic proteins (AAP)—that is overexpressed in several cancer pathologies. The apoptotic regulation is mediated through the binding of pro-apoptotic peptides (PAPs) (e.g., Bak and Bid) at the canonical hydrophobic binding groove (CBG) of Mcl1. Although all PAPs form amphipathic α-helices, their amino acid sequences vary to different degree. This sequence variation exhibits a central role in the binding partner selectivity towards different AAPs. Thus, constructing a novel peptide or small organic molecule with the ability to mimic the natural regulatory process of PAP is essential to inhibit various AAPs. Previously reported experimental binding free energies (BFEs) were utilized in the current investigation aimed to understand the mechanistic basis of different PAPs targeted to mMcl1. Molecular dynamics (MD) simulations used to estimate BFEs between mMcl1—PAP complexes using Molecular Mechanics-Generalized Born Solvent Accessible (MMGBSA) approach with multiple parameters. Predicted BFE values showed an excellent agreement with the experiment (R2 = 0.92). The van–der Waals (ΔGvdw) and electrostatic (ΔGele) energy terms found to be the main energy components that drive heterodimerization of mMcl1—PAP complexes. Finally, the dynamic network analysis predicted the allosteric signal transmission pathway involves more favorable energy contributing residues. In total, the results obtained from the current investigation may provide valuable insights for the synthesis of a novel peptide or small organic inhibitor targeting Mcl1." @default.
- W3045576747 created "2020-08-03" @default.
- W3045576747 creator A5049555415 @default.
- W3045576747 creator A5061052548 @default.
- W3045576747 creator A5061962424 @default.
- W3045576747 creator A5073986742 @default.
- W3045576747 date "2020-07-28" @default.
- W3045576747 modified "2023-10-06" @default.
- W3045576747 title "Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes" @default.
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- W3045576747 doi "https://doi.org/10.3390/biom10081114" @default.
- W3045576747 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7463671" @default.
- W3045576747 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32731448" @default.
- W3045576747 hasPublicationYear "2020" @default.
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