Free energy landscape and multiple folding pathways of an H-type RNA pseudoknot.

Yunqiang Bian,Wei Wang,Jun Wang,Jihua Wang,Jian Zhang,Emanuele Paci

doi:10.1371/journal.pone.0129089

Abstract

How RNA sequences fold to specific tertiary structures is one of the key problems for understanding their dynamics and functions. Here, we study the folding process of an H-type RNA pseudoknot by performing a large-scale all-atom MD simulation and bias-exchange metadynamics. The folding free energy landscapes are obtained and several folding intermediates are identified. It is suggested that the folding occurs via multiple mechanisms, including a step-wise mechanism starting either from the first helix or the second, and a cooperative mechanism with both helices forming simultaneously. Despite of the multiple mechanism nature, the ensemble folding kinetics estimated from a Markov state model is single-exponential. It is also found that the correlation between folding and binding of metal ions is significant, and the bound ions mediate long-range interactions in the intermediate structures. Non-native interactions are found to be dominant in the unfolded state and also present in some intermediates, possibly hinder the folding process of the RNA.

Highlights

As a major type of macromolecule essential for life, RNAs carry out numerous biological functions including translating genetic information into proteins, regulating gene expression, catalyzing biochemical process, etc
The stability of the RNA pseudoknot is mostly attributed to three groups of interactions, including the canonical base-base pairing within two helices and the non-canonical interactions between loop L2 and H1 (Fig 1A and 1C)
The native structure is very stable under the current force field, according to the 200ns-long conventional molecular dynamics (MD) simulation starting from the native structure

Summary

Introduction

As a major type of macromolecule essential for life, RNAs carry out numerous biological functions including translating genetic information into proteins, regulating gene expression, catalyzing biochemical process, etc. RNA pseudoknots are examples of minimal structural motifs in RNA with tertiary interactions They have been found play important roles in self-splicing, stimulating ribosomal frameshifting, forming the catalytic core, etc [1, 2]. In addition to their functional importance, RNA pseudoknots provide excellent models for studying the folding mechanism of RNAs. In addition to their functional importance, RNA pseudoknots provide excellent models for studying the folding mechanism of RNAs This is because they contain many types of interactions commonly seen in RNAs, including canonical and non-canonical base pairs, tertiary interactions such as the A-minor interactions often seen in loop-stem triplex, coaxial stacking, and the metal ion-nucleotides

Methods

Results

Conclusion