Simulating the RNA mirror world

Nucleotides are chiral molecules that can exist in two enantiomeric forms, behaving like mirror-images to each other. Yet in nature nucleotides exist nearly exclusively in D-form and not in the opposite L-form. Natural enzymes only recognize D-nucleotides, making the L-form resistant to enzymatic degradation and modification. This biological inertness is an amazing property, especially for molecular research and for pharmaceuticals, but it also means that L-RNA cannot be recognized and polymerized by natural polymerases. Until now, this has been the major bottleneck limiting the use of L-RNA, but ongoing advances in mirror-image polymerase might soon allow the easy production of L-RNA molecules. Many current applications of D-RNA, e.g. sensors like RNA thermometers or pharmaceuticals like RNA aptamers, could be “mirrored” to L-RNA versions that do not interact with enzymes or natural RNA binding partners. However, aside polymerization, there are many other issues that hinder the spread of L-RNA into R&D. One drawback is that all computational methods were made for D-RNA. The current RNA forcefields used for Molecular Dynamics have symmetry breaks, making them unfit to simulate L-RNA. Our first aim is to test the simulation of L-RNA aptamers and develop or adapt programs to work with L-RNA. As a starting point, we are using Nox-E36, the most established L-RNA aptamer drug on the market working against inflammatory diseases and cancer, as a starting point. As the binding constants between Nox-E36 and its target , the human chemokine CCL2, as well as other CCL proteins are known, we are trying to fit our simulations to reflect the experimental data of Nox-E36, e.g. by using a forcefield modification that was specifically designed for L-RNA. As second step, we want to use the obtained simulation parameters to identify novel, chemically modified versions of Nox-E36 having a better affinity and/or specificity towards CCL2, showing that our simulation parameters can be universally adapted to L-RNA aptamers

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