Free Energy Landscape of GAGA and UUCG RNA Tetraloops

TL;DR

This study uses advanced molecular dynamics simulations to estimate the folding free energies of specific RNA tetraloops, revealing discrepancies with experimental data and evaluating force field corrections.

Contribution

It introduces a novel approach combining parallel tempering, well-tempered metadynamics, and eRMSD for RNA folding thermodynamics estimation.

Findings

Native fold is not the global free energy minimum.

Estimated folding free energies significantly differ from experimental data.

Force field corrections improve but do not fully resolve accuracy issues.

Abstract

We report the folding thermodynamics of ccUUCGgg and ccGAGAgg RNA tetraloops using atomistic molecular dynamics simulations. We obtain a previously unreported estimation of the folding free energy using parallel tempering in combination with well-tempered metadynamics. A key ingredient is the use of a recently developed metric distance, eRMSD, as a biased collective variable. We find that the native fold of both tetraloops is not the global free energy minimum using the Amber\c{hi}OL3 force field. The estimated folding free energies are 30.2kJ/mol for UUCG and 7.5 kJ/mol for GAGA, in striking disagreement with experimental data. We evaluate the viability of all possible one-dimensional backbone force field corrections. We find that disfavoring the gauche+ region of {\alpha} and {\zeta} angles consistently improves the existing force field. The level of accuracy achieved with these corrections, however, cannot be considered sufficient by judging on the basis of available thermodynamic data and solution experiments.