Eric J. Sorin, Young Min Rhee, and Vijay S. Pande. Biophysical Journal (2005)
SUMMARY: While previous studies on the folding of nucleic acid hairpins have employed simplified models of either the nucleic acid or the solvent, this paper reports the first such study using an explicit treatment of the surrounding water and counterions. We show that accounting for water molecules in this manner is necessary to most accurately characterize the energetics of hairpin folding, whereas monovalent ions appear to play only a background role.
TECHNICAL ABSTRACT: Nucleic acid structure and dynamics are known to be closely coupled to local environmental conditions and, in particular, to the ionic character of the solvent. Here we consider what role the discrete properties of water and ions play in the collapse and folding of small nucleic acids. We study the folding of an experimentally well-characterized RNA hairpin-loop motif (sequence 5′-GGGC[GCAA]GCCU-3′) via ensemble molecular dynamics simulation and, with nearly 500 of aggregate simulation time using an explicit representation of the ionic solvent, report successful ensemble folding simulations, with a predicted folding time of 8.8(2.0)s, in agreement with experimental measurements of ~10s. Comparing our results to previous folding simulations using the GB/SA continuum solvent model shows that accounting for water-mediated interactions is necessary to accurately characterize the free energy surface and stochastic nature of folding. The formation of secondary structure appears to be more rapid than the fastest ionic degrees of freedom, and counterions do not participate discretely in observed folding events. We find that hydrophobic collapse follows a predominantly expulsive mechanism in which a diffusion-search of early structural compaction is followed by final formation of native structure that occurs in tandem with solvent evacuation.