Abstract: “Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease characterized by muscle wasting, myotonia, cardiac defects, and more. DM1 symptoms are caused by expanded RNAs, r(CUG)exp, that exist as imperfect hairpin structures and sequester alternative splicing regulators, such as muscleblind-like protein 1 (MBNL1). Our therapeutic approach is to rationally design small molecules that target r(CUG)exp and release MBNL1. One of the most accessible methods to assess probable ligand-RNA interactions is computational modeling. Molecular dynamics simulations allow for visualization of the possible binding modes of ligands and computations to assess their relative stabilities; coupled with experimental data, these simulations can provide useful insights to explain the relative binding strengths of different ligands. Molecular dynamics systems are neutralized with counterions to prevent electrostatic repulsions within nucleic acid molecules from skewing the results of the simulation. Generally, simulations are neutralized with a single counterion, such as sodium or magnesium. With the goal of better approximating cellular conditions in silico, we have developed a new neutralization scheme using cellular concentrations of magnesium, sodium, and potassium. We are currently validating the method via comparison to previously reported simulations.”
East Central IL ACS Undergraduate Research Conference
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Why is the simulation box set to 100 x 50 x 50 ang. Is that a minimum size for a certain number of interactions or does this size just make calculating the conc easy?
Thanks for your question John! The size of the box was determined by placing the edges of the box 15 Å from the nearest solute in each direction, which is a commonly used method to determine the size of an appropriate solvation box for a simulation (ie, we don’t want the RNA or ligand to fall out of the box during the simulation, but we have to balance that with the tradeoff of computational cost).