Abstract: “Myotonic-Dystrophy Type 1 (DM1) is a disease caused by the sequestration of splicing proteins, such as muscleblind-like 1 (MBNL1). The goal of this project is to find molecules that bind to RNA and inhibit MBNL protein sequestration. We used Myotonic-Dystrophy Type 1 (DM1) as a model system. I modeled a series of macrocyclic ligands in Molecular Operating Environment (MOE) using melamine or diaminopurine as a U-U mismatch recognition unit to target r(CUG)exp. The linker length of the ligands was varied to create stable macrocycles with promising hydrogen bonding. The results of these simulations can be coupled with experimental data to better our understanding of DM1 and ligand-RNA interactions.”
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Very nice presentation, I was wondering if you could explain how the modeling was done. In particular what theoretical viewpoint was used. Was this using molecular mechanics, ab-initio, or some other method? For whichever method, could you provide the parameters that were chosen for the modeling?
We started with a mutated crystal structure (RNA with CUG repeats) and then docked the ligand onto it. There were no molecular mechanics involved, we just minimized using MOE.
You state that you modeled various macrocycles; however, there is only one presented. What variations did you compare? How did you assess which were better than others? Did you observe any trends that will influence your design of new molecules to model?
We varied the macrocycles a few ways. With the melamine macrocycles, we varied the length of each linker as well as the exact location of the functional groups along that linker. We then did the same thing with diaminopurine. We will also test those same macrocycles in different bonding situations with the U bases (i.e. flip out or triplet).
We determined which macrocycles were best first by the number of hydrogen bonds preserved between the ligand and the U bases. Then we looked at the stability of the molecule and the ease with which it can be synthesized. The one presented was one of the better examples, achieving 8 hydrogen bonds and being relatively stable. As far as trends go, it’s still too soon to say, although the ultimate goal of the project is definitely to achieve some sort of model for future design, which I am hopeful toward given the promising start.