Restraint-Biased 2D Molecular Dynamics Simulations

Although recent experimental and computational advances have strived to understand RNA structure-function relationships, the roles of many RNAs are dependent upon a complex network of motifs, including hairpins, internal loops, pseudoknots and long-range contacts, that are not easily captured by these methods. Ab-initio modeling using all atom molecular dynamics simulations is limited by the available energy functions and the required sampling of an extensive conformational space. We have developed a hybrid replica exchange method that incorporates secondary structure information from experiments in the form of piecewise linear-harmonic distance restraints (bias forces) to efficiently fold RNA in 3D detail. This sharpens the free energy landscape by reducing the number of conformations that satisfy an optimum 3D fold. Replica exchange conducted in both temperature and position space, where replicas with variable bias forces and temperatures run in parallel and periodically swap, also allows molecules to overcome kinetic barriers surrounding local minima. A range of possible structures are uncovered from higher temperatures, but only the most stable conformations are retained at lower temperatures.