Computational Analysis of Molecular Recognition in DNA Base-Sequence and Groove by Methidium Chloride Using Molecular Mechanics Calculation

Takeo KONAKAHARAa*, Harunobu KOMATSUa, Norio SAKAIa and Barry GOLDb

aDepartment of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science
Noda, Chiba 278-8510, Japan
bEppley Institute for Research in Cancer and Allied Diseases
University of Nebraska Medical Center, Omaha, NE 68198-680, U.S.A.

(Received: August 10, 2006; Accepted for publication: September 25, 2006; Published on Web: December 21, 2006)

Computational analysis of minor and major groove methidium-DNA complexes in B-form DNA 5'-d(CATCCCGGGATG) is performed for intercalation at each base pair. The most stable structure based on stabilization energies was calculated by a combination of molecular mechanics (augmented MM2) and molecular dynamics (MD) methods. When methidium intercalates from the minor groove, the phenanthridine ring is parallel to the nucleobase pairs, and the excluded site size is 6.4 A. The stabilization is maximal when the methidium intercalates between 5'-d(CG) from the minor groove (-28.3 kcal.mol-1). Calculations using MD showed that the complex was considerably less stable when the methidium intercalated from the major groove. This result is consistent with experimental results demonstrating that the intercalation of methidium occurs from the minor groove. A plot of the calculated stabilization energy vs. the logarithm of the binding constant of ethidium bromide with each dinucleotide affords a linear relationship.

Keywords: Molecular Recognition, Molecular Mechanics, Molecular Dynamics, DNA Intercalation, Methidium, Groove Selectivity

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