PHYS 356 |
| Y-family DNA polymerases are susceptible to error-prone DNA synthesis where potentially catastrophic single base deletion mutations, which completely change the downstream genetic code, can occur with much greater frequency than other DNA polymerases. Recent crystal structures of a Y-family DNA polymerase DinB precisely clarify the atomic details of the base flipped intermediates that corrupt the incorporation of the correct nucleotide, but the dynamic mechanism of introduction of single base deletion mutations is not fully understood. To formulate such an understanding, free energy profiles of specific single base flipping processes were computed using umbrella sampling molecular dynamics (MD) simulations in combination with a coarse-grained pseudodihedral restraint that enforces base flipping through the minor and major groove pathways. The calculated free energy profiles for three different cytosines in the presence and absence of the protein environment quantitatively characterize the influence of the protein structure and dynamics in DNA replication by the DinB enzyme. The results allow prediction of a coarse-grained mechanism for incorporation of a single base deletion mutation in DNA biosynthesis, which can be extended to explain the fidelity of DNA replication by higher accuracy polymerases. |
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PHYS Poster Session - Multiscale Modeling in Biophysics
7:30 PM-10:00 PM, Wednesday, April 9, 2008 Morial Convention Center -- Hall A, Poster
Sci-Mix
Division of Physical Chemistry |