How biological molecules move electrons: Simplicity trumps complexity

November 03, 1999

In a sweeping new study, researchers at the University of Pennsylvania Medical Center have shown that the natural engineering principles governing electron transfer within proteins are significantly less complex than has been the prevailing view. Of the many parameters influencing the movement of electrons within biological molecules, proximity alone of the electron's origin and destination points appears to be sufficient to promote the necessary transfers: They must be no more than 14 angstroms apart.

Electron transfers of the kind investigated represent the fundamental atomic-level exchanges that underpin the energy economies of all living things. They occur between so-called reduction-oxidation centers, or redox centers, within proteins. Reduction is the receipt of an electron, and oxidation is the release of an electron. The transfers are accomplished by means of a nearly instantaneous quantum mechanical phenomenon called tunneling: The electrons tunnel through the protein from one redox center to the next. About a third of all known proteins are electron-transfer proteins.

The new findings have some important implications. They suggest, first, that many of the long-analyzed structural details of electron-transfer proteins did not evolve as necessary to their function, but are instead the happenstance result of other factors. Nature, it would appear, recognizes a point of diminishing returns in the evolutionary refinement of biological mechanisms, opting in this case for a flexible, more robust system over an optimized, finely tuned one that might be more vulnerable to disruption by mutations. Second, the results point to a greatly simplified approach to the design of entirely new biologically active molecules, likely to be of immediate use in drug development efforts, and construction of such molecules is already under way at Penn. A report on the study appears in the November 4 issue of Nature.

"What we're saying in this study is that many facets of these biological molecules thought to be exquisitely evolved and critical to their function are not so," says P. Leslie Dutton, PhD, chairman of the department of biochemistry and biophysics, director of the Johnson Research Foundation at Penn, and senior author on the report. "Instead, nature has evolved the redox centers in the molecules just to be close enough to each other to effectively promote electron tunneling. For tunneling, that and only that is the relevant characteristic that's evolved."

"There's a widely accepted idea that electrons get from one redox center to another in a protein by traveling down a series of molecular bonds that describe a best pathway," adds coauthor Christopher C. Moser, PhD, associate director of the Johnson Research Foundation. "What we've found is that there's nothing special about that pathway. It has not been designed, per se. Instead, evolution ignores the structure of the protein medium between two points and uses only proximity to assure that the electron transfer rates are fast enough to satisfy the needs of biology."

For the current study, the Penn team surveyed the structures of all naturally occurring molecules with multiple redox centers in the Protein Data Bank (PDB), a database managed by the Research Collaboratory for Structural Bioinformatics, a consortium composed of Rutgers, the State University of New Jersey; the University of California at San Diego; and the National Institute of Standards and Technology. The PDB contains more than 10,000 structures. Using statistical techniques, the researchers looked for patterns in certain characteristics of the electron-transfer process. These were the free energy or driving force behind the electron transfer, the reorganization energy associated with the movement of atoms after the transfer, the packing density of the atoms in the protein between redox centers, and the distance in angstroms between redox centers. The results demonstrated that the only parameter consistently required to guide the electron tunneling function was that the redox centers be within 14 angstroms of each other. For electron transfers over greater distances, the molecules used redox centers in series, spaced no more than 14 angstroms apart.

The lead author on the study is Christopher C. Page, BS. With Moser and Dutton, the remaining author is Xiaoxi Chen, PhD. Funding for the work was provided by the National Institutes of Health.
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The University of Pennsylvania Medical Center's sponsored research and training ranks second in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation - $201 million in federal fiscal year 1998. In addition, the institution continued to maintain the largest absolute growth in funding for research and training among all 125 medical schools in the country since 1991. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page ( http://www.med.upenn.edu ), to EurekAlert! ( http://www.eurekalert.org ), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news service Newswise ( http://www.newswise.com ).

University of Pennsylvania School of Medicine

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