I. A novel computational methodology for identifying RNA minimum sequence requirements for ligand binding and recognition. II. Fluorine force field parameterization and modeling of organic fluorine

I. Small RNAs play a critical role in many biological processes, including the regulation of gene expression, and are valuable drug targets. Identifying the minimum sequence requirements of RNA binding to small molecules can enhance understanding of RNA-ligand molecular recognition and aid in drug design or target selection. Experimental techniques for identifying small RNAs that target specific ligands do not necessarily reveal the simplest RNAs that bind the ligand. As detailed in Section I, we have developed a computational method that combines molecular dynamics simulations and free-energy techniques to determine minimum sequences of RNAs required for selective ligand binding. This method has allowed 33-nucleotide (nt) and 35-nt RNAs targeting theophylline and FMN, respectively, to be truncated to just 13 nt and 14 nt. The truncated RNAs maintain selective binding to their targets as shown by binding studies. Furthermore, the method has allowed accurate prediction of the RNA minimum binding sequence for the aminoglycoside antibiotic paromomycin. The molecular dynamics simulations also allow insights into the energetics and mechanism of molecular recognition of the truncated RNA structures.;II. The introduction of fluorine into a molecule can greatly influence the molecule's physicochemical properties. The interactions between highly fluorinated molecules are of considerable interest and have relevance to phase-separation phenomena and the fluorophobic effect. As shown in Section II, we have performed molecular modeling studies of highly fluorinated alkane molecules that seek to address two specific aspects of fluorine interactions. First, a set of non-bonded force field parameters for fluorine has been developed for the accurate modeling of bulk liquids of perfluorinated n -alkanes by molecular mechanics. These parameters allow accurate prediction of important thermodynamic parameters of the liquids, including enthalpies of vaporization and molar volumes. Second, ab initio calculations have been performed to evaluate the effect of the degree of fluorination of methane on its interaction energies with the lithium cation. These calculations show that increasing the number of fluorine atoms in the methane molecule decreases the interaction energy with lithium cation. The decrease in interaction energy is associated with decreased electrostatic potential mapped to the fluoromethane molecular surface.