Minor groove deformability of DNA: A Molecular dynamics free energy simulation study
Martin Zacharias 1*
1 International University Bremen
* To whom correspondence should be addressed. E-mail: m.zacharias{at}iu-bremen.de.
Submitted on February 20, 2006
Revised on March 12, 2006
Accepted on 14 April 2006
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Abstract |
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The conformational deformability of nucleic acids can influence its function and recognition by proteins. A class of DNA binding proteins including the TATA box binding protein bind to the DNA minor groove resulting in an opening of the minor groove and DNA bending towards the major groove. Explicit solvent molecular dynamics (MD) simulations in combination with the umbrella sampling approach have been performed to investigate the molecular mechanism of DNA minor groove deformations and the indirect energetic contribution to protein binding. As a reaction coordinate the distance between backbone segments on opposite strands was used similar to a reaction coordinate employed in restraint energy minimization studies (Lebrun, A., Z. Shakked, and R. Lavery 1997. Local DNA stretching minics the distortion caused by the TATA box-binding protein. Proc. Natl. Acad. Sci. USA 94:2993-2998.). The resulting deformed structures showed close agreement with experimental DNA structures in complex with minor groove binding proteins. The calculated free energy of minor groove deformation was ~4-6 kcal mol-1 in case of a central TATATA sequence. A smaller equilibrium minor groove width and more restricted minor groove mobility was found for the central AAATTT and also a significantly (~two-times) larger free energy change for opening the minor groove. The helical parameter analysis of trajectories indicates that an easier partial unstacking of a central TA vs. AT basepair step is a likely reason for the larger groove flexibility of the central TATATA case.
Key Words:
DNA bending, DNA recognition, free energy calculation, nucleic acid flexibility, potential of mean force, protein DNA binding
