Molecular Simulations to Investigate the Impact of N6-Methylation in RNA Recognition: Improving Accuracy and Precision of Binding Free Energy Prediction.

N6-Methyladenosine (mA) is a prevalent RNA post-transcriptional modification that plays crucial roles in RNA stability, structural dynamics, and interactions with proteins. The YT521-B (YTH) family of proteins, which are notable mA readers, functions through its highly conserved YTH domain. Recent structural investigations and molecular dynamics (MD) simulations have shed light on the mechanism of recognition of mA by the YTHDC1 protein.

Alchemical Metadynamics: Adding Alchemical Variables to Metadynamics to Enhance Sampling in Free Energy Calculations.

Performing alchemical transformations, in which one molecular system is nonphysically changed to another system, is a popular approach adopted in performing free energy calculations associated with various biophysical processes, such as protein-ligand binding or the transfer of a molecule between environments. While the sampling of alchemical intermediate states in either parallel (e.g.

Molecular Simulations Matching Denaturation Experiments for N-Methyladenosine.

Post-transcriptional modifications are crucial for RNA function and can affect its structure and dynamics. Force-field-based classical molecular dynamics simulations are a fundamental tool to characterize biomolecular dynamics, and their application to RNA is flourishing. Here, we show that the set of force-field parameters for N-methyladenosine (mA) developed for the commonly used AMBER force field does not reproduce duplex denaturation experiments and, specifically, cannot be used to describe both paired and unpaired states.