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First Principles Calculations of the Tautomers and pK_a Values of 8-Oxoguanine: Implications for Mutagenicity and Repair

Jang, Yun Hee and Goddard, William A., III and Noyes, Katherine T and Sowers, Lawrence C and Hwang, Sungu and Chung, Doo Soo (2002) First Principles Calculations of the Tautomers and pK_a Values of 8-Oxoguanine: Implications for Mutagenicity and Repair. Chemical Research in Toxicology, 15 (8). pp. 1023-1035. ISSN 0893-228X. https://resolver.caltech.edu/CaltechAUTHORS:20170409-074336222

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Abstract

8-Oxoguanine is a mutagenic oxidative damage product of guanine that has been the subject of many experimental studies. Despite numerous references to this damaged base, its precise configuration or population of configurations in equilibrium are unknown, as it can be drawn in over 100 potential neutral and ionized tautomeric forms. The structural uncertainty surrounding 8-oxoguanine complicates mechanistic studies of its mutagenicity and capacity to be recognized for repair. Experimental measurements on the tautomeric equilibria and pK_a values of 8-oxoguanine are complicated by its insolubility in water. Therefore, we used first principles quantum mechanics (density functional theory, B3LYP, in combination with the Poisson−Boltzmann continuum-solvation model) to investigate the relative stabilities and site-specific pK_a values of various neutral and ionized tautomers of 8-oxoguanine. We show that the major tautomer of neutral 8-oxoguanine in aqueous solution is the 6,8-diketo form 2, and that 8-oxoguanine has increased acidity at N1 relative to guanine. Our calculations on 2‘-deoxyguanosine-3‘,5‘-bisphosphate and its 8-oxo analogue support the accepted conclusion that repulsion between the O8 of 8-oxoguanine and O5‘ of the backbone sugar promote 8-oxoguanine:adenine pairings in the syn:anti conformation. Further, we show that the N7 proton of 8-oxoguanine is difficult to remove either through tautomerization or ionization, consistent with its involvement as an important landmark in distinguishing guanine from 8-oxoguanine. The possibility of additional structural landmarks that distinguish 8-oxoguanine from guanine, and a possible mechanism for glycosylase removal of 8-oxoguanine are discussed.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/tx010146rDOIArticle
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
Chung, Doo Soo0000-0002-8335-3201
Additional Information:© 2002 American Chemical Society. Received September 6, 2001. This work was supported in part by the National Institutes of Health [HD36385 (W.A.G), GM 41336 (L.C.S.), and CA 85779 (L.C.S. and W.A.G.)], the BK21 program and the CMC of Korea (Y.H.J., S.H., and D.S.C.). The computations were aided by an SUR grant from IBM. In addition, the facilities of the MSC are also supported by DOE-ASCI, ARO-MURI, ARO-DURIP, National Science Foundation [CHE-99-85574 and 99-77872], Dow Chemical, 3M, Beckman Institute, Avery-Dennison, Chevron Corporation, Seiko Epson, Asahi Chemical, and Kellogg's.
Funders:
Funding AgencyGrant Number
NIHHD36385
NIHGM 41336
NIHCA 85779
BK21 ProgramUNSPECIFIED
IBMUNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Army Research Office (ARO)UNSPECIFIED
NSFCHE-99-85574
NSFCHE-99-77872
Dow Chemical CompanyUNSPECIFIED
3MUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Avery-DennisonUNSPECIFIED
Chevron CorporationUNSPECIFIED
Seiko-EpsonUNSPECIFIED
Asahi ChemicalUNSPECIFIED
Kellogg'sUNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20170409-074336222
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170409-074336222
Official Citation:First Principles Calculations of the Tautomers and pKa Values of 8-Oxoguanine:  Implications for Mutagenicity and Repair Yun Hee Jang, William A. Goddard III, Katherine T. Noyes, Lawrence C. Sowers, Sungu Hwang, and Doo Soo Chung Chemical Research in Toxicology 2002 15 (8), 1023-1035 DOI: 10.1021/tx010146r
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76440
Collection:CaltechAUTHORS
Deposited By: 1Science Import
Deposited On:24 May 2017 22:27
Last Modified:09 Mar 2020 13:18

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