| Summary: | BCL-2 proteins play a significant role in regulating apoptosis through complex interactions between antiapoptotic and apoptotic members. In cancer cells, the overexpression of antiapoptotic proteins inhibit the heterodimerization of apoptotic proteins, preventing cell death. Hence, through studies focusing on key interactions between BH3 domains of apoptotic proteins and antiapoptotic proteins, insights which are constructive towards the development of novel anticancer drugs that mimic the functionality of BH3 domains can be attained. Molecular dynamics (MD) simulations have been well developed along with robust computational analytical tools, and become a standard approach used to study peptide-protein binding. In this thesis, through MD simulations, the impact caused by the length of the BH3 peptide in BAX when bound to antiapoptotic protein BCL-2 was studied. By comparing the 26-mer and 21-mer BAX peptides, the C-terminus residues of BH3 peptide were revealed having the ability to maintain the α helix and, at the same time, stabilise the salt-bridge between peptide and protein. Further, more BCL-2/BH3 complexes are studied to identify the influence of peptide sequence on binding affinity. Detailed information on both hydrophobic and hydrophilic residues was obtained by analysing multiple simulations for each complex. Furthermore, hotspots of BCL-2 were identified. Although having similar binding scenario, BH3 peptides from different BH3-only proteins selectively bind to antiapoptotic proteins and through MD simulations and energy decomposition, this recognition between BH3-only proteins and antiapoptotic proteins were identified. Crucial sequence and dynamic difference of BCL-xL and MCL-1 were also discussed. All the detailed information on the BCL-2 family at molecular level was intended to offer insights towards future drug design based on the binding mechanism between BCL-2 family members.
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