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Article

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes

1
Structural Bioinformatics Laboratory (SBL), Biochemistry and Pharmacy, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland
2
PLASMANT Research Group, Chemistry Department, University of Antwerp, 2610 Antwerp, Belgium
3
Department of Future Technologies, Faculty of Science and Engineering, University of Turku, FI-20014 Turku, Finland
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(8), 1114; https://doi.org/10.3390/biom10081114
Received: 18 June 2020 / Revised: 16 July 2020 / Accepted: 24 July 2020 / Published: 28 July 2020
(This article belongs to the Section Molecular Structure and Dynamics)
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. View Full-Text
Keywords: B-cell lymphoma 2; myeloid cell leukemia; binding free energy; protein interaction network; allosteric-signaling pathway B-cell lymphoma 2; myeloid cell leukemia; binding free energy; protein interaction network; allosteric-signaling pathway
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MDPI and ACS Style

Marimuthu, P.; Razzokov, J.; Singaravelu, K.; Bogaerts, A. Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes. Biomolecules 2020, 10, 1114. https://doi.org/10.3390/biom10081114

AMA Style

Marimuthu P, Razzokov J, Singaravelu K, Bogaerts A. Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes. Biomolecules. 2020; 10(8):1114. https://doi.org/10.3390/biom10081114

Chicago/Turabian Style

Marimuthu, Parthiban, Jamoliddin Razzokov, Kalaimathy Singaravelu, and Annemie Bogaerts. 2020. "Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide—Mcl1 Complexes" Biomolecules 10, no. 8: 1114. https://doi.org/10.3390/biom10081114

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