Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis

Abstract

B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer 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 (ΔG_ele) contributions are the major component that drives the interaction between Bak peptides and different anti-apoptotic peptides. Additionally, van der Waals (ΔG_vdw) 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.

Keywords:

• anti-apoptotic proteins
• pro-apoptotic peptides
• heterodimerization
• binding free energy
• molecular dynamics simulations

Acknowledgements

M.P. gratefully acknowledges the use of bioinformatics infrastructure facility supported by Biocenter Finland; CSC-IT Center for Science (Project: AA1268 and 2000461) for computational facility; and grants from the Joe, Pentti, and Tor Borg Memorial Fund and the Sigrid Juselius Foundation; Dr. Jukka Lehtonen for the IT support; Dr. Sabarinathan Radhakrishnan, Institute for Research in Biomedicine, Barcelona, Spain, for the MD analysis script; and specially thank Prof. Mark Johnson, Åbo Akademi University for providing the lab facility.