Abstract
Ribonucleic acids (RNAs) are key to the central dogma of molecular biology. While Raman spectroscopy holds great potential for studying RNA conformational dynamics, current computational Raman prediction and assignment methods are limited in terms of system size and inclusion of conformational exchange. Here, a framework is presented that predicts Raman spectra using mixtures of sub-spectra corresponding to major conformers calculated using classical and ab initio molecular dynamics. Experimental optimization allowed purines and pyrimidines to be characterized as predominantly syn and anti, respectively, and ribose into exchange between equivalent south and north populations. These measurements are in excellent agreement with Raman spectroscopy of ribonucleosides, and previous experimental and computational results. This framework provides a measure of ribonucleoside solution populations and conformational exchange in RNA subunits. It complements other experimental techniques and could be extended to other molecules, such as proteins and carbohydrates, enabling biological insights and providing a new analytical tool.
Highlights
Ribonucleic acids (RNAs) are key to the central dogma of molecular biology
Deciphering the spectral complexity associated with large RNAs and assigning the constituent bands is a problem limiting the utility of Raman spectroscopy[16]
We achieve experimental agreement, opening up Raman spectroscopy as a simple, inexpensive experimental route to 3D-structure determination of nucleic acids to complement existing techniques. While we demonstrate this for the first time on RNA ribonucleoside building blocks, it may have fundamental applicability to a wide range of other molecules
Summary
Ribonucleic acids (RNAs) are key to the central dogma of molecular biology. While Raman spectroscopy holds great potential for studying RNA conformational dynamics, current computational Raman prediction and assignment methods are limited in terms of system size and inclusion of conformational exchange. The importance of including conformational exchange in Raman spectral predictions was confirmed by sampling 1000 3D-structures from each Boltzmann-weighted MD conformer distribution using aqueous molecular dynamics simulations and a force-field optimized for RNA (OPLS-AA/M). Local conformer dynamics were sampled for the syn/south conformer region per nucleoside, resulting in spectral linewidths that were broadened to within close agreement with experiment (Fig. 3).
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