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

Parthiban Marimuthu,Kalaimathy Singaravelu,Annemie Bogaerts,Jamoliddin Razzokov

doi:10.3390/biom10081114

Parthiban Marimuthu, Kalaimathy Singaravelu + Show 2 more

Open Access

https://doi.org/10.3390/biom10081114

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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.

Highlights

Apoptosis—programmed cell death—is an essential biological mechanism that is regulated by the B-cell lymphoma 2 (Bcl-2) family proteins [1]
This information is used in the current investigation as the starting point to explore the molecular basis of different proteins or their BH3 domain peptides (PAPs) binding to mMcl1
The Molecular dynamics (MD) simulations revealed that the polar contacts, i.e., the salt bridge and the hydrogen bond formed between conserved aspartic acid of PAPs and the R244 and N241 residue of mMcl1, help to stabilize the complex in all the cases

Summary

Introduction

Apoptosis—programmed cell death—is an essential biological mechanism that is regulated by the B-cell lymphoma 2 (Bcl-2) family proteins [1]. Bcl-2 proteins exhibit their apoptotic activity either via pro-apoptotic proteins or their BH3 domain peptides (PAPs) or anti-apoptotic proteins (AAPs), or both [2]. The anti-apoptotic Bcl-2 family members—such as Bcl-2, Bcl-xL, Bcl-w, Mcl (myeloid cell leukemia 1) and Bfl-1/A1 [3]—are characterized by pathological cell survival. AAP mediates the central role as the attractive therapeutic targets in several human diseases, such as cancer and autoimmune disorders [4]. Among the Bcl-2 family members, Mcl appears to be a critical survival factor in several cancer pathologies [5,6,7,8,9]. This causes the escape of cancerous cells from the natural apoptotic process, resulting in uncontrolled cell proliferation, and multi-drug resistance [10]

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