| dc.identifier.uri | http://hdl.handle.net/11401/77812 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Every day the genome sustains endogenous and exogenous damage, which is reversed by various repair pathways. One of the most prevalent types of damage, 8-oxoguanine (8OG), arises when a normal guanine base is oxidized, resulting in only a two atom difference from guanine in normal DNA. This type of damage is insidious, however; 8OG mispairs with adenine upon replication, giving rise to a transversion mutation from which the original DNA sequence cannot be recovered. To protect the genome from high mutation rates, the bacterial protein Formamidopyrimidine DNA glycosylase (Fpg) is responsible for searching DNA, recognizing the 8OG lesion when it is paired in a canonical Watson-Crick hydrogen bonding pattern opposite cytosine, promoting eversion of the 8OG out of the helix and into its active site where excision occurs. The dynamic aspects of recognition and base eversion have proved difficult to characterize using experiments. In this work, all-atom molecular dynamics simulations are used to model the recognition and repair pathway, and connect structure, dynamics, and energy. Due to the long timescale of these events, a time-independent method called partial nudged elastic band has been developed and used to link two crystal structures and predict the conformational rearrangements along a minimum energy pathway. Umbrella sampling can then be used to calculate the free energy surface along this pathway for transitions of interest. This method is used to probe the groove preference of the everting 8OG base. The simulations indicate 8OG is bound by Fpg in a conformation preferred by the damage, and is displaced towards the major groove. Eversion occurs through the major groove where there is a 3-4 kcal/mol free energy barrier, presenting a lower barrier to eversion than the minor groove pathway, which has a calculated 7-8 kcal/mol barrier. | |
| dcterms.available | 2017-09-26T16:40:37Z | |
| dcterms.contributor | Scharer, Orlando | en_US |
| dcterms.contributor | Simmerling, Carlos | en_US |
| dcterms.contributor | Wang, Jin | en_US |
| dcterms.contributor | Roitberg, Adrian. | en_US |
| dcterms.creator | Bergonzo, Christina | |
| dcterms.dateAccepted | 2017-09-26T16:40:37Z | |
| dcterms.dateSubmitted | 2017-09-26T16:40:37Z | |
| dcterms.description | Department of Chemistry. | en_US |
| dcterms.extent | 150 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77812 | |
| dcterms.identifier | Bergonzo_grad.sunysb_0771E_10994.pdf | en_US |
| dcterms.issued | 2012-05-02 | |
| dcterms.language | en_US | |
| dcterms.provenance | Submitted by Jason Torre (fjason.torre@stonybrook.edu) on 2017-09-26T16:40:37Z
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Bergonzo_grad.sunysb_0771E_10994.pdf: 6633564 bytes, checksum: 7e5085dbe7f7591923c25930759db7a2 (MD5) | en |
| dcterms.provenance | Made available in DSpace on 2017-09-26T16:40:37Z (GMT). No. of bitstreams: 1
Bergonzo_grad.sunysb_0771E_10994.pdf: 6633564 bytes, checksum: 7e5085dbe7f7591923c25930759db7a2 (MD5)
Previous issue date: 2012-05-01 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Chemistry | |
| dcterms.subject | biochemistry, computational, dynamics, theoretical | |
| dcterms.title | Understanding the Recognition Mechanism of Repair Protein Fpg: Development and Application of Ensemble Approaches to Long Timescale Dynamics | |
| dcterms.type | Dissertation | |
