Molecular Modeling of the Intrastrand Guanine-Guanine DNA Adducts Produced by Cisplatin and Oxaliplatin
- 1Department of Medicine and Cancer Center (E.D.S., S.B.H.), and2Department of Pharmacology (J.M.B.), University of California, San Diego, La Jolla, California
Abstract
Intrastrand DNA adducts formed by cisplatin and oxaliplatin were modeled with molecular mechanics minimization and restrained molecular dynamics simulations in a comparative study. A reasonable set of force field parameters for the Pt atom were refined by using the available cisplatinated DNA crystal structure as a guide. This crystal structure was also used as the starting structure for the simulations. Analysis of the resulting structures indicated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference between the two structures resulted from the presence of the 1,2-diaminocyclohexane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major groove of the bound DNA, forming a markedly altered and less polar major groove in the area of the adduct. The differences in the structure of the adducts produced by cisplatin and oxaliplatin are consistent with the observation that they are differentially recognized by the DNA mismatch repair system.
Footnotes
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Send reprint requests to: Stephen B. Howell, M.D., Department of Medicine 0058, UCSD Cancer Center, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0058. E-mail: showell{at}ucsd.edu
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↵1 Present address: San Diego Supercomputer Center 0537, University of California, San Diego, La Jolla, California.
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↵2 Present address: Department of Biology and Biochemistry, University of Houston, Houston, Texas.
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This work was supported by a search contract from Sanofi Research (Malvern, PA). This work was conducted in part by Clayton Foundation for Research—California Division. Dr. Howell is a Clayton Foundation investigator. A preliminary account of this work was presented at the 1998 Annual Meeting of the American Association for Cancer Research [Abstract no. 1082, Proc Am Assoc Cancer Res39:158]
- Abbreviations:
- DACH
- diaminocyclohexane
- AMBER
- assisted model building with energy refinement
- MD
- molecular dynamics
- MMR
- DNA mismatch repair
- PDB
- Protein Data Bank
- RMS
- root mean squared
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- Received January 11, 1999.
- Accepted May 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
