Mechanism of the Oxaliplatin Binding to the Double-Stranded 1,2-ds(pGpG) Dinucleotide in Aqueous Solution


Zdeněk Chval,a Martin Kabeláč,b,c and Jaroslav V. Burdad


a Department of Laboratory Methods and Medical Technology, Faculty of Health and Social Studies, University of South Bohemia, J. Boreckého 27, 370 11 České Budějovice, Czech Republic

b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic

c Department of Chemistry, Faculty of Natural Sciences, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic

d Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic.


A mechanism of the formation of the intrastrand 1,2-crosslink between ds(pGpG) dinucleotide and hydrolyzed oxaliplatin is studied using theoretical RI-DFT-D and ONIOM/MP2/B3LYP methods. It is a two-step reaction in which the monoadduct formation is the rate-determining step with activation free energy of ~ 20 kcal/mol followed by the diadduct formation step with activation free energy of ~ 15 kcal/mol. The binding in the 5’-G → 3’-G direction is kinetically preferred over the 3’-G → 5’-G direction. Non-bonded interactions and steric effects influence considerably the structure of transition states affecting energetics of the reaction. The overall reaction is exergonic by more than 20 kcal/mol. The changes of the ds(pGpG) structure and charge transfer effects upon the oxaliplatin binding will be discussed.


We gratefully acknowledge support from the Grant Agency of the Czech Republic (grants 204/09/J010 and P205/10/0228) and from the Ministry of Education, Youth and Sports of the Czech Republic (grants ME09062 and ME10149).