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

Biomolecules. 2020 Jul 28;10(8):1114. doi: 10.3390/biom10081114.

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.

Keywords: B-cell lymphoma 2; allosteric-signaling pathway; binding free energy; myeloid cell leukemia; protein interaction network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Drug Design*
  • Humans
  • Molecular Dynamics Simulation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / chemistry
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Thermodynamics

Substances

  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptides