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Femtosecond dynamics of a drug-protein complex: Daunomycin with Apo riboflavin-binding protein

Zhong, Dongping and Pal, Samir Kumar and Wan, Chaozhi and Zewail, Ahmed H. (2001) Femtosecond dynamics of a drug-protein complex: Daunomycin with Apo riboflavin-binding protein. Proceedings of the National Academy of Sciences of the United States of America, 98 (21). pp. 11873-11878. ISSN 0027-8424. PMCID PMC59816. https://resolver.caltech.edu/CaltechAUTHORS:ZHOpnas01b

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Abstract

In this contribution, we report studies of the primary dynamics of the drug-protein complexes of daunomycin with apo riboflavin-binding protein. With femtosecond resolution, we observed the ultrafast charge separation between daunomycin and aromatic amino acid residues of the protein, tryptophan(s). Electron transfer occurs from tryptophan(s) to daunomycin with two reaction times, 1 ps and 6 ps, depending on the local complex structure. The formation of anionic daunomycin radical is crucial for triggering a series of chemical reactions in redox cycling. One of the subsequent reactions is the reduction of dioxygen to form active superoxide by the reduced daunomycin. This catalytic process was found to occur within 10 ps. In the absence of dioxygen, charge recombination takes a much longer time, more than 100 ps. These results, along with similar findings in DNA and nucleotides, elucidate that the ultrafast generation of reduced daunomycin radicals by photoactivation is a primary step for the observed photoenhancement of drug cytotoxicity by several orders of magnitude. We also studied the dependence of the dynamics on protein conformations at different ionic strengths and denaturant concentrations. We observe a sharp transition from the tertiary structure to the unfolding state at 2 M of denaturant concentration.


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Additional Information:© 2001, The National Academy of Sciences. Contributed by Ahmed H. Zewail, August 20, 2001. We thank Prof. Hugo L. Monaco (University of Verona, Italy) for providing the riboflavin-binding protein coordinates, and Dr. Hans-Christian Becker for discussion and help. This work was supported by the National Science Foundation. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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Subject Keywords:daunomycin, tryptophan, apo riboflavin-binding protein, electron transfer, guanidine hydrochloride
Issue or Number:21
PubMed Central ID:PMC59816
Record Number:CaltechAUTHORS:ZHOpnas01b
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:ZHOpnas01b
Official Citation:Dongping Zhong, Samir Kumar Pal, Chaozhi Wan, and Ahmed H. Zewail Femtosecond dynamics of a drug–protein complex: Daunomycin with Apo riboflavin-binding protein PNAS 2001 98 (21) 11873-11878; doi:10.1073/pnas.211440298
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:505
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:11 Jul 2005
Last Modified:02 Oct 2019 22:34

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