Ab initio molecular dynamics reveals striking reorganization of the trinuclear metal cluster of endonuclease IV during catalysis

BIOL 189

Ivaylo Ivanov, iivanov@mccammon.ucsd.edu, Department of Chemistry & Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0365, John A. Tainer, jat@scripps.edu, Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB4, San Diego, CA 92037, and J. Andrew McCammon, jmccammon@ucsd.edu, Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093-0365.
Endonuclease IV belongs to a class of important AP endonucleases involved in DNA repair. Although a structure-based mechanistic hypothesis has been suggested, its detailed catalytic mechanism has remained unknown. Using ab initio molecular dynamics we determined that the catalytic transformation proceeded through a synchronous bimolecular (ANDN) mechanism with reaction free energy and barrier of -3.5 and 20.6 kcal/mol, repectively. During the reaction the active site underwent dramatic local conformational changes – shifts in the coordination mode of both substrate and first-shell ligands. This finding supports the notion that structural rearrangements in the active sites of multinuclear enzymes are integral to biological function.
 

Enzymes
4:30 PM-6:30 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006