Coarse-Grained Model for Predicting RNA Folding Thermodynamics

Abstract

We present a thermodynamically robust coarse-grained model to simulate folding of RNA in monovalent salt solutions. The model includes stacking, hydrogen bond, and electrostatic interactions as fundamental components in describing the stability of RNA structures. The stacking interactions are parametrized using a set of nucleotide-specific parameters, which were calibrated against the thermodynamic measurements for single-base stacks and base-pair stacks. All hydrogen bonds are assumed to have the same strength, regardless of their context in the RNA structure. The ionic buffer is modeled implicitly, using the concept of counterion condensation and the Debye-Hückel theory. The three adjustable parameters in the model were determined by fitting the experimental data for two RNA hairpins and a pseudoknot. A single set of parameters provides good agreement with thermodynamic data for the three RNA molecules over a wide range of temperatures and salt concentrations. In the process of calibrating the model, we establish the extent of counterion condensation onto the single-stranded RNA backbone. The reduced backbone charge is independent of the ionic strength and is 60% of the RNA bare charge at 37 °C. Our model can be used to predict the folding thermodynamics for any RNA molecule in the presence of monovalent ions.