Apoptosis is a key cell death pathway in mammalian cells. Understanding this process and its regulation has been a subject of study in the last three decades. Members of the Bcl-2 family of proteins are involved in the regulation of apoptosis through mitochondrial poration with the subsequent initiation of apoptosis. Deregulation of proapoptotic proteins contributes to the progression of many tumor processes. Understanding how these pore-forming Bcl-2 proteins Bak and Bax are activated is key to find new anticancer treatments. As no drug capable of activating Bak has been disclosed yet, the study of the structural features of BH3 peptides-known as Bak activators-relevant for binding along with its binding energy decomposition analysis, becomes essential for designing novel small-molecule mimics of BH3. Interestingly, a BH3 Bim analogue-inactivating Bak has recently been discovered, opening a question on the molecular features that determine the functions of BH3 peptides. Therefore, the present work is aimed at understanding the way BH3 peptides activate or inactivate Bak in order to identify differential structural features that can be used in drug design. For this purpose, complexes of Bak with an activator and an inhibitor have been subjected to a molecular dynamics study. Structural differences were assessed by means of the fluctuations of the corresponding principal components. Moreover, the MMPB/GBSA approach was used to compute the binding free energy of the diverse complexes to identify those residues of the BH3 peptide that exhibit the larger contributions to complex formation. The results obtained in this work show differences between activators and inhibitors, both in structural and energetic terms, which can be used in the design of new molecules that can activate or inactivate proapoptotic Bak.

中文翻译：

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BH3肽激活/抑制Bak蛋白的分子决定因素。

凋亡是哺乳动物细胞中的关键细胞死亡途径。在过去的三十年中，了解这一过程及其规律一直是研究的主题。Bcl-2蛋白家族的成员通过线粒体穿孔参与细胞凋亡的调控，并随后引发细胞凋亡。促凋亡蛋白的失调有助于许多肿瘤过程的进展。了解这些成孔的Bcl-2蛋白Bak和Bax如何被激活是寻找新的抗癌治疗方法的关键。由于尚未公开能够激活Bak的药物，对BH3肽的结构特征（称为Bak激活剂）的研究及其结合能分解分析对于结合具有重要意义，因此对于设计新颖的BH3小分子模拟物至关重要。有趣的是 最近发现了一种BH3 Bim类似物失活的Bak，这对决定BH3肽功能的分子特征提出了疑问。因此，本工作旨在了解BH3肽激活或灭活Bak的方式，以鉴定可用于药物设计的不同结构特征。为此，已经对Bak与活化剂和抑制剂的复合物进行了分子动力学研究。通过相应主要成分的波动来评估结构差异。此外，MMPB / GBSA方法用于计算各种复合物的结合自由能，以鉴定BH3肽对复合物形成具有较大贡献的那些残基。