Survivin - caspase protein-protein interaction: Experimental evidence and computational investigations to decipher the hotspot residues for drug targeting

Abstract Survivin is an Inhibitor of Apoptosis (IAP) family protein that is involved in various protein-protein interactions (PPIs) and thereby regulates cell division, apoptosis, and autophagy. Besides, survivin is overexpressed in most of the human solid tumors, but not in differentiated normal cells. Hence, identification of survivin PPI hotspots could pave way for effective structure-based drug design. For this, we used both in vitro (proximity ligation assay) and in silico (protein-protein docking and molecular dynamics simulation) methods to understand survivin PPI interaction with caspase-3, caspase-7, and caspase-9 in the absence/presence of XIAP BIR domains. Computational results reveal that survivin interacts with the catalytic site and/or at the dimerization site of caspase-3, caspase-7, and caspase-9. This PPI could inhibit the catalytic activity of caspases and hinder apoptosis in cancer. Moreover, MM-PBSA binding energy calculation disclosed that survivin strongly interacts with all three caspases in the presence of XIAP BIR domains. Additionally, per-residue energy decomposition results revealed that survivin BIR domain residues Asp53, Glu65, Gly66, Glu68, Asp70, Asp71, and Glu76, and C-α helix residues Glu125, Lys129, Arg132, and Arg133 significantly contributed to binding with the caspases. Targeting these hotspot residues with small molecules could result in the disruption of survivin-caspase PPI, leading to the induction of apoptosis in cancer.