SUNY at Albany
June 19-23, 2001
The Free Energy and Structural Pathways of Base Flipping in DNA
Base flipping is a structural mechanism by which a base in a DNA double helix can be accessed by DNA modification and repair enzyme active sites. Earlier theoretical studies suggested that base flipping occurs spontaneously only through the major groove of DNA. Protein-DNA crystal structures, however, indicate that both the major groove and minor groove flipping pathways may be used by base-flipping enzymes. To address this problem, umbrella sampling free energy calculations were performed on DNA in an explicit solvent environment. To study the free energy profile or potential of mean force (PMF) of base flipping, a center-of-mass (COM) dihedral constraint method was implemented in the biomolecular simulation program CHARMM. The novel COM dihedral constraint allowed for base flipping intermediates along both the minor and major groove flipping pathways to be sampled. The free energy profile calculated suggests that the energy barrier heights for the minor groove and major groove pathways are similar. This observation, which is contrary to previous beliefs, suggests that either pathway can be used to attain the fully flipped state of the target base. The local structural details of the two flipping pathways and the energetic contributions involved are discussed.
Nilesh K Banavali* and Alexander D. MacKerell, Jr.
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