Molecular Determinants for the Activation/Inhibition of Bak Protein by BH3 Peptides
| Autor: | Jaime Rubio-Martinez, Juan J. Perez, José M. Granadino-Roldán, Guillem Vila-Julià |
|---|---|
| Přispěvatelé: | Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial |
| Rok vydání: | 2020 |
| Předmět: |
Programmed cell death
General Chemical Engineering Apoptosis Bak Protein Molecular dynamics Library and Information Sciences Biology 01 natural sciences Enginyeria química [Àrees temàtiques de la UPC] Proto-Oncogene Proteins 0103 physical sciences Animals Dinàmica molecular 010304 chemical physics Cancer--Treatment Apoptosi General Chemistry Peptide Fragments 0104 chemical sciences Computer Science Applications Cell biology 010404 medicinal & biomolecular chemistry bcl-2 Homologous Antagonist-Killer Protein Càncer -- Tractament Pèptids biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins Peptides |
| Zdroj: | UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.9b01047 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|