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

PLoS One. 2015 Jun 1;10(6):e0129089. doi: 10.1371/journal.pone.0129089. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Kinetics
  • Models, Molecular*
  • Molecular Dynamics Simulation*
  • Nucleic Acid Conformation*
  • RNA / chemistry*
  • RNA / genetics*
  • Thermodynamics*

Substances

  • RNA

Grants and funding

National Natural Science Foundation of China (NSFC) Grants No. 11274157 JZ http://nsfc.pubmed.cn, National Natural Science Foundation of China (NSFC) Grants No. 11174133 JW http://nsfc.pubmed.cn, National Basic Research Program of China (NBRPC) Grants No. 2012CB921502 JZ http://www.973.gov.cn, National Basic Research Program of China (NBRPC) Grants No. 2013CB834100 WW http://www.973.gov.cn, National Natural Science Foundation of China (NSFC) Grants No. 11334004 WW http://nsfc.pubmed.cn, Priority Academic Program Development of Jiangsu Higher Education Institutions JZ http://jsycw.ec.js.edu.cn.