Condensation of Nucleic Acids by Multivalent Ions: Sequence Dependence and the Curious Case of RNA

Abstract

Highly charged nucleic acid (NA) molecules repel each other in monovalent salt solutions, yet can be condensed by multivalent ions into structured aggregates. This phenomenon is of great significance to biology, biotechnology and medicine. Surprisingly, recent experiments (Physical Review Letters 2011, 106, 108101; Nucleic Acids Research 2014, 42, 10823) demonstrate that short double-stranded RNA helices resist condensation under conditions where short DNA duplexes condense readily. Existing theoretical models of the NA condensation can not satisfactorily explain this striking differences in RNA vs. DNA condensation behavior. We combine experiment, atomistic molecular dynamics simulations and theory to propose a mechanism that connects the observed variations in condensation of short NA duplexes by trivalent cobalt hexammine and tetravalent spermine cations with a spatial variation of bound counterion charge atthe NA duplex surface. Specifically, NA condensation propensity is determined by the fraction of neutralizing multivalent counterions charge localized at the external (outermost) surface of the double-helix. A simple model is developed that provides semi-quantitative agreement with experiment, including subtle sequence effects on condensation propensity. Latest developments and experimental verification of the model will also be discussed.