%0 Journal Article
%A Baik, Mu-Hyun
%A Friesner, Richard A.
%A Lippard, Stephen J.
%D 2003
%T Theoretical Study of Cisplatin Binding to Purine Bases: Why
Does Cisplatin Prefer Guanine over Adenine?
%U https://acs.figshare.com/articles/journal_contribution/Theoretical_Study_of_Cisplatin_Binding_to_Purine_Bases_Why_Does_Cisplatin_Prefer_Guanine_over_Adenine_/3654675
%R 10.1021/ja036960d.s001
%2 https://acs.figshare.com/ndownloader/files/5744076
%K barrier heights
%K continuum solvation model
%K hydrogen bond forms
%K purine base site
%K Utilizing density
%K anticancer activity
%K platinated purine bases
%K chloride ligand
%K transition state
%K guanine bases
%K Cisplatin Binding
%K model reactants
%K Theoretical Study
%K DNA
%K MO analysis
%K monofunctional binding
%K antitumor drug cisplatin
%K monofunctional platination
%K Cisplatin Prefer Guanine
%K energy decomposition
%K adenine
%K hydrogen bond
%X 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 ΔG‡ = ∼23 kcal/mol
for the monofunctional platination of guanine, our model gives ΔG‡ = 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 OC6 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 H2N−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.
%I ACS Publications