Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1

Marimuthu, Parthiban; Razzokov, Jamoliddin; Eshonqulov, G. B.

doi:10.1016/j.ijbiomac.2020.04.243

Cited by 6 publications

(2 citation statements)

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“…This finding was strengthened when two independent sets of randomized BH3-like sequences derived from each of five wild-type pro-apoptotic BH3 peptides were tested with Mcl-1 or Bcl-X L . Although the previous studies have identified polar interactions between specific residues responsible for high binding affinity or specificity, ,,, current studies show that the long-range interactions as a result of the overall acidic or basic nature of the peptide can determine the specificity and affinity of BH3-like peptides for either Mcl-1 or Bcl-X L .…”

Section: Discussionmentioning

confidence: 55%

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues

et al. 2020

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Interactions between pro-and anti-apoptotic B cell lymphoma 2 (Bcl-2) proteins decide the fate of the cell. BH3 (Bcl-2 homology 3) domain of pro-apoptotic Bcl-2 proteins interacts with the exposed hydrophobic groove of anti-apoptotic counterparts. Design and development of BH3 mimetics that target the hydrophobic groove of specific anti-apoptotic Bcl-2 proteins have the potential to become anti-cancer drugs. We have developed a novel computational method to design sequences with BH3 domain features that can bind specifically to anti-apoptotic Mcl-1 or Bcl-X L . In this method, we retained the four highly conserved hydrophobic and aspartic residues of wild-type BH3 sequences and randomly substituted all other positions to generate a large number of BH3-like sequences. We modeled 20000 complex structures with Mcl-1 or Bcl-X L using the BH3-like sequences derived from five wild-type pro-apoptotic BH3 peptides. Peptideprotein interaction energies calculated from these models for each set of BH3-like sequences resulted in negatively-skewed extreme value distributions. The selected BH3-like sequences from the extreme negative tail regions have distinctly different distribution of charged residues for Mcl-1 and Bcl-X L . BH3-like sequences with highly favorable interaction energies prefer to have acidic residues for Mcl-1 and are enriched with basic residues when they bind to Bcl-X L .With the charged residues often away from the binding interface, the overall electric field generated by the charged residues result in highly favorable long-range electrostatic interaction energies between the peptide and the protein giving rise to high specificity. Cell viability studies of representative BH3-like peptides further validated the predicted specificity.

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Section: Discussionmentioning

confidence: 55%

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues

et al. 2020

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“…Previously, several studies have been carried out on different Bcl-2 family proteins using various MD simulation approaches. These investigations revealed (i) the driving force behind the intra-molecular conformational change [ 58 ], (ii) the helix stability [ 59 , 60 ], (iii) crucial residues involved in heterodimerization [ 61 ] (iv) crucial molecular properties responsible for complexity [ 62 , 63 , 64 ] (v) hot-spot residues [ 65 ] (vi) effects of Bim mutants [ 66 ] and (vii) the inter-helical interactions across families [ 67 ]. Based on this information, we attempted to explore the mMcl1—PAP complexes to extend our understanding of the molecular mechanism of heterodimerization by identifying the key features.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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.

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In silico design of potential Mcl-1 peptide-based inhibitors

Faraji,

Daly,

Arab

et al. 2024

J Mol Model

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Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1

Cited by 6 publications

References 60 publications

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues

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

In silico design of potential Mcl-1 peptide-based inhibitors

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Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1

Cited by 6 publications

References 60 publications

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-XL: Role of Non-Hot Spot Residues

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-XL: Role of Non-Hot Spot Residues

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

In silico design of potential Mcl-1 peptide-based inhibitors

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Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues

Computational Design of BH3-Mimetic Peptide Inhibitors That Can Bind Specifically to Mcl-1 or Bcl-X_L: Role of Non-Hot Spot Residues