Effects of Molecular Dynamics and Replica Exchange Molecular Dynamics in Sampling the Conformational Space of PARP-1

Sampling the conformational space of target proteins is pivotal to understand their functions and improve structure-based drug discovery approaches.1 Apart from molecular dynamic simulations (MD),2 other computational methods have been developed with the aim of increasing the capacity of sampling the conformational space of proteins. In this framework, replica exchange molecular dynamics (REMD)3 is emerging as one of the methods of choice. In the first part of this study we report a comparative assessment of the performance of MD and REMD in sampling the conformational space of an important anticancer drug target, namely PARP-1.4 In the second part of the work, we demonstrate that binding site conformations generated with MD and REMD simulations improve the performance of docking experiments of a library of known active and inactive PARP-1 inhibitors with the respect to an ensemble of PARP-1 crystal structures.