PARP1, a multidomain enzyme that recognizes DNA damages, plays a crucial role for DNA repair and genome integrity. Its inhibition has been investigated as therapeutic opportunity for different pathologies including cancers, diabetes, stroke and cardiac failure. Two different inhibitors of PARP1 sharing a similar binding mode and same affinities for the enzyme have different efficacies. It has been experimentally shown that Olaparib traps PARP1 on DNA damaged sites, causing a so-called “poisoning effect”, whereas Veliparib is devoid of such activity. The current study is aimed at understanding why and how these two ligands act differently. Molecular dynamic simulations of the apo and holo forms of PARP1 in complex with Olaparib and Veliparib have been performed, using ACEMD. As a result, ligand-induced conformational differences have been highlighted between Olaparib simulation and the two other simulations that may account for the different poisoning effect of these inhibitors. Overall, this study led to the identification of the signaling pathway that promotes the cross-talks between the functional domains of PARP1 using the Wordom program.
1μs Molecular Dynamics Simulations to study the poisoning effect of the PARP-1 full length enzyme
CAROTTI, Andrea;CAMAIONI, Emidio;PELLICCIARI, Roberto;MACCHIARULO, Antonio
2014
Abstract
PARP1, a multidomain enzyme that recognizes DNA damages, plays a crucial role for DNA repair and genome integrity. Its inhibition has been investigated as therapeutic opportunity for different pathologies including cancers, diabetes, stroke and cardiac failure. Two different inhibitors of PARP1 sharing a similar binding mode and same affinities for the enzyme have different efficacies. It has been experimentally shown that Olaparib traps PARP1 on DNA damaged sites, causing a so-called “poisoning effect”, whereas Veliparib is devoid of such activity. The current study is aimed at understanding why and how these two ligands act differently. Molecular dynamic simulations of the apo and holo forms of PARP1 in complex with Olaparib and Veliparib have been performed, using ACEMD. As a result, ligand-induced conformational differences have been highlighted between Olaparib simulation and the two other simulations that may account for the different poisoning effect of these inhibitors. Overall, this study led to the identification of the signaling pathway that promotes the cross-talks between the functional domains of PARP1 using the Wordom program.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
