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 (ΔG_vdw) and electrostatic (ΔG_ele) 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.

中文翻译：

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预测的热点残基参与促凋亡肽-Mcl1复合物中的变构信号传递。

Mcl1是Bcl-2家族的主要成员-抗凋亡蛋白（AAP）-在几种癌症病理中均过表达。凋亡调控是通过促凋亡肽（PAP）（例如Bak和Bid）在Mcl1的规范疏水结合槽（CBG）上的结合而介导的。尽管所有PAP均形成两亲性α螺旋，但其氨基酸序列不同程度地变化。该序列变异在针对不同AAP的结合伴侣选择性中显示出核心作用。因此，构建具有模拟PAP天然调节过程能力的新型肽或有机小分子对于抑制各种AAP至关重要。先前报道的实验性结合自由能（BFE）用于当前的研究中，旨在了解针对mMcl1的不同PAP的机制基础。分子动力学（MD）模拟用于使用mMcl1-PAP复合物之间的BFE进行估计，该方法使用了分子力学-通用的无溶剂通用（MMGBSA）方法进行。预测的BFE值与实验具有很好的一致性（R ²＝ 0.92）。发现范德华（_ΔGvdw）和静电（_ΔGele）能量项是驱动mMcl1-PAP配合物异二聚化的主要能量成分。最后，动态网络分析预测了变构信号传输途径涉及更有利的能量贡献残基。总体而言，从当前的研究中获得的结果可能为合成靶向Mcl1的新型肽或有机小抑制剂提供有价值的见解。