The Molecular Basis for Polymerase-beta Fidelity During DNA Repair
EMSL Project ID
2270
Abstract
Computational modeling studies of polymerase beta (pol b) will be carried out to provide novel insight into the role that protein dynamics plays in Pol b fidelity. If molecular dynamics were found to play an important role in determining Pol b fidelity, these studies would provide a basis for examining polymorphism variations and how they might alter dynamics and fidelity. It is probable that the Mg2+ ions play the role of a trigger in much of the chemistry associated with BER. Hence, it is essential to understand the structure and bonding of this essential metal during as many stages as possible in the reactions involving Pol b. This level of detail is conveniently studied by computational techniques, and provides an essential understanding of the consequences of polymorphisms in the central proteins within the BER process. The proposed molecular simulations will be carried out to evaluate the induced-fit hypothesis as the primary mechanism for selectivity of Pol b. In particular, we will address the conformational rearrangements induced upon binding of the correct and incorrect nucleotide for the template DNA strand, and the resulting changes in active site conformation and DNA-protein affinity. The molecular dynamics simulations will be designed to determine how protein dynamics and metals influence the organization of the catalytic residues of pol b and facilitate the transition state chemistry. Computer simulations will be carried out on 32-64 processors using the NWCHEM molecular dynamics capabilities. Requested time: 6,000 Jupiter node hours. Results of this work will be used as preliminary data for a computational grand challenge application.
Project Details
Project type
Capability Research
Start Date
2001-06-07
End Date
2001-10-01
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members