Investigating molecular interaction between TDP1 and PARP1

DNA topoisomerase is responsible for regulation of DNA topology. Topoisomerase I (topoI) cleaves and rejoins the DNA single strand by forming a transient covalent complex with DNA via a phosphodiester bond. Tyrosyl-phosphodiesterase 1 (TDP1) catalyzes the hydrolysis of the phosphodiester bond between an active site tyrosine in HtopoI and DNA 3’-phosphate making TDP1 functionally connected with HtopoI activity. N-terminal domain (NTD) of TDP1 interacts with C-terminal domain (CTD) of Poly [ADP-ribose] polymerase 1 (PARP1) and gets PARylated that enhances recruitment of TDP1 to DNA damage sites. Herein, we investigated molecular interaction of complex formation between TDP1 and PARP1. We modelled a full-length PARP1 and obtained the TDP1-PARP1 complex using molecular docking. Molecular dynamics simulations were utilized to study structural integrity of the predicted complex and to investigate the residues involved in the formation of the TDP1-PARP1 complex. Surface plasmon resonance (SPR)-based experimental approach resulted in a KD value of ∼5 nM for the binding between these two functionally important proteins.