Theoretical Study of DNA Damage Recognition via Electron Transfer from the [4Fe-4S] Complex of MutY

¹ University of Maryland
² UC Davis
³ University of California at Davis

^* To whom correspondence should be addressed. E-mail: cox{at}physics.ucdavis.edu.

Submitted on February 26, 2008
Revised on April 1, 2008
Accepted on 11 June 2008

	Abstract

The mechanism of site-specific recognition of DNA by proteins has been a long standing issue. The DNA glycosylase MutY, for instance, must find the rare 8-oxoguanine-adenine mismatches among the large number of base pairs in the DNA. This protein has a [4Fe-4S] cluster, which is highly conserved in species as diverse as E. Coli and Homo Sapiens. The mixed valence nature of this cluster suggests that charge transfer may play a role in MutY's function. We have studied the energetics of the charge transfer in Bacillus stearothermophilus MutY-DNA complex using multi-scale calculation including Density Functional Theory and Molecular Dynamics. The [4Fe-4S] cluster in MutY is found to undergo 2+ to 3+ oxidation when coupling to DNA through hole transfer, especially when MutY is near an oxoguanine modified base (oxoG). Employing the Marcus theory for electron transfer, we find near optimal Frank-Condon (FC) factors for electron transfer from MutY to oxoG. MutY has modest selectivity for oxoguanine over guanine due to the difference in oxidation potential. The tunneling matrix element is significantly reduced with the mutation R149W, while the mutation L154F reduces the tunneling matrix element as well as the FC factor. Both L154F and R149W mutations are known to dramatically reduce or eliminate repair efficiency. We suggest a scenario where the charge transfer leads to a stabilization of the specific binding conformation, which is likely the recognition mode, thus enabling it to find the damage site efficiently.

Key Words: DNA oxidative damage, MutY, density functional theory, electron transfer, molecular dynamics, multi-scale modeling