A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis
Tekijät: Parthiban Marimuthu, Kalaimathy Singaravelu
Kustantaja: Taylor and Francis Ltd.
Julkaisuvuosi: 2018
Journal: Journal of Biomolecular Structure and Dynamics
Tietokannassa oleva lehden nimi: Journal of Biomolecular Structure and Dynamics
Vuosikerta: 36
Numero: 6
Aloitussivu: 1637
Lopetussivu: 1648
Sivujen määrä: 12
ISSN: 0739-1102
DOI: https://doi.org/10.1080/07391102.2017.1331863
Tiivistelmä
membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins. In light of discovering the novel peptide/drug molecules that contain the potential to inhibit specific anti-apoptotic protein, it is necessary to understand the molecular basis of recognition between the protein and its binding partner (peptide or ligand) along with its binding energies. Therefore, the present work focused on deciphering the molecular basis of recognition between pro-apoptotic Bak peptide binding to different anti-apoptotic (Bcl-xL, Bfl-1, Bcl-W, Mcl-1, and Bcl-2) proteins using advanced Molecular Dynamics (MD) approach such as Molecular Mechanics-Generalized Born Solvent Accessible. The results from our investigation revealed that the predicted binding free energies showed excellent correlation with the experimental values (r2 = .95). The electrostatic (ΔGele) contributions are the major component that drives the interaction between Bak peptides and different anti-apoptotic peptides. Additionally, van der Waals (ΔGvdw) energies also play an indispensible role in determining the binding free energy. Furthermore, the decomposition analysis highlighted the comprehensive information about the energy contributions of hotspot residues involved in stabilizing the interaction between Bak peptide and different anti-apoptotic proteins.
membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins. Additionally, the heterodimerization displayed differences in binding affinity profile among the pro-apoptotic peptides binding to anti-apoptotic proteins. In light of discovering the novel peptide/drug molecules that contain the potential to inhibit specific anti-apoptotic protein, it is necessary to understand the molecular basis of recognition between the protein and its binding partner (peptide or ligand) along with its binding energies. Therefore, the present work focused on deciphering the molecular basis of recognition between pro-apoptotic Bak peptide binding to different anti-apoptotic (Bcl-xL, Bfl-1, Bcl-W, Mcl-1, and Bcl-2) proteins using advanced Molecular Dynamics (MD) approach such as Molecular Mechanics-Generalized Born Solvent Accessible. The results from our investigation revealed that the predicted binding free energies showed excellent correlation with the experimental values (r2 = .95). The electrostatic (ΔGele) contributions are the major component that drives the interaction between Bak peptides and different anti-apoptotic peptides. Additionally, van der Waals (ΔGvdw) energies also play an indispensible role in determining the binding free energy. Furthermore, the decomposition analysis highlighted the comprehensive information about the energy contributions of hotspot residues involved in stabilizing the interaction between Bak peptide and different anti-apoptotic proteins.
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