Theoretical study of cisplatin binding to purine bases: why does cisplatin prefer guanine over adenine?
The thermodynamics and kinetics for the monofunctional binding of the antitumor drug cisplatin, cis-diamminedichloroplatinum(II), to a purine base site of DNA were studied computationally using guanine and adenine as model reactants. A dominating preference for initial attack at the N7-position of guanine is established experimentally, which is a crucial first step for the formation of a 1,2-intrastrand cross-link of adjacent guanine bases that leads to bending and unwinding of DNA. These structural distortions are proposed ultimately to be responsible for the anticancer activity of cisplatin. Utilizing density functional theory in combination with a continuum solvation model, we developed a concept for the initial Pt-N7 bond formation to atomic detail. In good agreement with experiments that suggested DeltaG++ = approximately 23 kcal/mol for the monofunctional platination of guanine, our model gives DeltaG++ = 24.6 kcal/mol for guanine, whereas 30.2 kcal/mol is computed when adenine is used. This result predicts that guanine is 3-4 orders of magnitude more reactive toward cisplatin than adenine. A detailed energy decomposition and molecular orbital analysis was conducted to explain the different barrier heights. Two effects are equally important to give the preference for guanine over adenine: First, the transition state is characterized by a strong hydrogen bond between the ammine-hydrogen of cisplatin and the O=C6 moiety of guanine in addition to a stronger electrostatic interaction between the two reacting fragments. When adenine binds, only a weak hydrogen bond forms between the chloride ligand of cisplatin and the H(2)N-C6 group of adenine. Second, a significantly stronger molecular orbital interaction is identified for guanine compared to adenine. A detailed MO analysis is presented to provide an intuitive view into the different electronic features governing the character of the Pt-N7 bond in platinated purine bases.
Baik
Mu-Hyun
MH
Department of Chemistry, Columbia University, New York, NY 10027, USA. mbaik@indiana.edu
Friesner
Richard A
RA
Lippard
Stephen J
SJ
D000225:Adenine / Q000737:chemistry* / Q000378:metabolism*; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism*; D006147:Guanine / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D013379:Substrate Specificity; D013816:Thermodynamics
D006147:Guanine; D000225:Adenine; D002945:Cisplatin