Molecular dynamics, MD, simulations of nucleic acids have seen major advances in recent years including improved force fields that result in structures comparable to those observed experimentally.  As a result, the sequence-dependence of structural parameters of nucleic acids (such as twist, slide, roll, minor groove width, major groove width, and BI/BII populations) can be examined by MD simulation.  In addition to exploring sequence effects, our group has investigated how the presence of the polyamide minor groove binder formamido-imidazole-pyrrole- imidazole, f-IPI, affects the nucleic acid structural parameters of its target sequence: 5'-CCACGCGT GG-3', the Mlu1 Cell Cycle Box (MCB) promoter site in the Dbf4 gene which is critical in the S-phase of the cell cycle.   The polyamide f-IPI binds to the MCB promoter site with an affinity more than 100 times greater than the naturally occurring minor groove binder distamycin binds to its AT-rich target sequence.MD simulations were conducted for 50 ns each on the DNA alone and in the presence of the f-IPI minor groove binder (both in 0.15 M NaCl /TIP3P water) using AMBER 12 with the ff99pbsc0 force field within the AMBER 12 package.  Comparisons of the nucleic acid structural parameters from both simulations will be presented and implications for improving binding affinity will be discussed.

Molecular dynamics simulation of a 2:1 polyamide minor groove binder/DNA complex: Nucleic acid structural parameters of the Mlu1 cell cycle box

247th National Meeting (2014)

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