[Fe4S4]-containing proteins participate in charge transfer and related redox signaling relevant to cell function. The Y345C mutation in the DNA-binding domain of primase (which has been identified in gastric tumors) can affect the binding of the RNA/DNA duplex to the C-terminal domain of primase and alter charge hopping pathways between the [Fe4S4] cluster and the duplex. This in turn impacts the signaling dynamics and endogenous repair function of primase. In this study, we first developed a python module that is able to map and rank hopping pathways in proteins according to the mean residence time of the transferring charge in such pathways. We then parameterized the high-potential [Fe4S4] cluster in its 2+ and 3+ redox states for molecular dynamics simulations. The effects of the mutation on the structure, dynamics, hole hopping pathways between the [Fe4S4] cluster and the duplex, and DNA-binding free energy will be described. We will also examine the electrostatic contributions to the binding free energies of the duplex to primase in both redox states. This analysis aims to examine the molecular origins of the experimentally observed strong dependence of the DNA binding affinity on the charge state of the [Fe4S4] cluster.

Unraveling functional hole hopping pathways in the [4Fe4S]-containing DNA primase

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.