Cooperativity Mechanisms and Hybridization Free-Energy Landscapes of Model Oligonucleotides In Solution

A coarse-grained lattice model of oligonucleotides is proposed to study the role of cooperativity in the microscopic pathways and mechanisms of DNA hybridization in solution; the extent to which this transition conforms to two-state thermodynamics is also analyzed. The thermodynamic behavior of this model have been extensively investigated and shown to correspond, qualitatively, to that observed in experiment. Equilibrium populations of single- and double-stranded states, and their associated free-energy landscapes, are calculated by Monte Carlo simulations with configurational bias and parallel tempering. The two-state nature of the transition is found to exhibit strong sequence dependence. Two general scenarios are found depending on the characteristics of the free-energy surface, in which hybridization pathways are shown to evolve through a complex network of stationary points, i.e., local minima and transition states. Remarkably, although hybridization of model oligonucleotides in solution always exhibits two-state thermodynamic signatures, its reaction pathways evolve, to a varying degree, through non-two-state mechanisms that involve stable and metastable intermediates.