Staring at the naked Goddess. Unraveling structure and reactivity of Artemis endonuclease interacting with a DNA double strand.

Abstract

Artemis is an endonuclease responsible for breaking hairpin DNA strand during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, or the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulation, both classically and at hybrid quantum mechanics/ molecular mechanics level, we evidence the stable interaction modes of Artemis with a model DNA strand. We also analyze the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.