Mutation effects on charge transport through the p58c iron-sulfur protein.

Published

Journal Article

Growing experimental evidence indicates that iron-sulfur proteins play key roles in DNA repair and replication. In particular, charge transport between [Fe4 S4 ] clusters, mediated by proteins and DNA, may convey signals to coordinate enzyme action. Human primase is a well studied [Fe4 S4 ] protein, and its p58c domain (which contains an [Fe4 S4 ] cluster) plays a role in the initiation of DNA replication. The Y345C mutation in p58c is linked to gastric tumors and may influence the protein-mediated charge transport. The complexity of protein-DNA systems, and the intricate electronic structure of [Fe4 S4 ] clusters, have impeded progress into understanding functional charge transport in these systems. In this study, we built force fields to describe the high potential [Fe4 S4 ] cluster in both oxidation states. The parameterization is compatible with AMBER force fields and enabled well-balanced molecular dynamics simulations of the p58c-RNA/DNA complex relevant to the initiation of DNA replication. Using the molecular mechanics Poisson-Boltzmann and surface area solvation method on the molecular dynamics trajectories, we find that the p58c mutation induces a modest change in the p58c-duplex binding free energy in agreement with recent experiments. Through kinetic modeling and analysis, we identify key features of the main charge transport pathways in p58c. In particular, we find that the Y345C mutation partially changes the composition and frequency of the most efficient (and potentially relevant to the biological function) charge transport pathways between the [Fe4 S4 ] cluster and the duplex. Moreover, our approach sets the stage for a deeper understanding of functional charge transfer in [Fe4 S4 ] protein-DNA complexes.

Full Text

Duke Authors

Cited Authors

  • Teo, RD; Migliore, A; Beratan, DN

Published Date

  • July 2020

Published In

Volume / Issue

  • 11 / 27

Start / End Page

  • 7076 - 7085

PubMed ID

  • 33250976

Pubmed Central ID

  • 33250976

Electronic International Standard Serial Number (EISSN)

  • 2041-6539

International Standard Serial Number (ISSN)

  • 2041-6520

Digital Object Identifier (DOI)

  • 10.1039/d0sc02245d

Language

  • eng