Atomistic view of base flipping in DNA.

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TitleAtomistic view of base flipping in DNA.
Publication TypeJournal Article
Year of Publication2004
AuthorsHuang, N, Mackerell, AD
JournalPhilos Trans A Math Phys Eng Sci
Volume362
Issue1820
Pagination1439-60
Date Published2004 Jul 15
ISSN1364-503X
KeywordsBase Pairing, Base Sequence, DNA, DNA Methylation, DNA Repair, DNA-Binding Proteins, Elasticity, Models, Molecular, Molecular Sequence Data, Motion, Nucleic Acid Conformation, Nucleic Acid Denaturation, Nucleic Acid Heteroduplexes, Quantum Theory, Stress, Mechanical, Structure-Activity Relationship, Torque
Abstract

Base flipping is essential for the enzyme-catalysed methylation of DNA. In our previous studies, the flipping of bases out of duplex DNA in DNA alone and when bound to the (cytosine-C5)-methyltransferase from HhaI (M.HhaI) were investigated via potential of mean force calculations. Insights into various experimental observations were obtained. In the present paper we present an overview of previous computational studies of base flipping along with new detailed structural and energetic analysis on atomic events that contribute to the free energy surfaces. The contributions from different intrinsic and environmental effects to the base-flipping process are explored, and experimental data derived from a variety of methods are reconciled. A detailed protein-facilitated base-flipping mechanism is proposed. Ground-state destabilization is achieved via disruption of the target base Watson-Crick interactions by substitution with favourable DNA-protein interactions. In addition, specific DNA-protein interactions and favourable solvation effects further promote target base flipping along the major groove through the protein matrix, and maximal interactions occur between the DNA and the protein upon reaching the fully flipped state. Other DNA binding proteins that involve distortion of DNA's conformation may use a similar mechanism to that by which M.HhaI facilitates base flipping.

DOI10.1098/rsta.2004.1383
Alternate JournalPhilos Trans A Math Phys Eng Sci
PubMed ID15306460
Grant ListGM 51501 / GM / NIGMS NIH HHS / United States