Thermal titration molecular dynamics (TTMD): shedding light on the stability of RNA-small molecule complexes

Abstract

Ribonucleic acids are gradually becoming relevant players among putative drug targets, thanks to the increasing amount of structural data exploitable for the rational design of selective and potent binders that can modulate their activity. Mainly, this information allows employing different computational techniques for predicting how well would a ribonucleic-targeting agent fit within the active site of its target macromolecule. Due to some intrinsic peculiarities of complexes involving nucleic acids, such as structural plasticity, surface charge distribution, and solvent-mediated interactions, the application of routinely adopted methodologies like molecular docking is challenged by scoring inaccuracies, while more physically rigorous methods such as molecular dynamics require long simulation times which hamper their conformational sampling capabilities. In the present work, we present the first application of Thermal Titration Molecular Dynamics (TTMD), a recently developed method for the qualitative estimation of unbinding kinetics, to characterize RNA-ligand complexes. In this article, we explored its applicability as a post-docking refinement tool on RNA in complex with small molecules, highlighting the capability of this method to identify the native binding mode among a set of decoys across various pharmaceutically relevant test cases.