Thermodynamics and Kinetics of Nucleobase Stacking Oligomerization Revealed by Molecular Dynamics Simulations

The aggregation of N6N9-dimethyladenine in aqueous solution into stacked oligomers represents an important model system for oligomerization processes. Molecular dynamics simulations allowed us to extract statistically converged stacking thermodynamics as well as converged association and dissociation kinetics. The simulations confirm an oligomerization mechanism according to a random isodesmic stacking model without significant cooperative effects. Multiple oligomerization and dissociation events were used to characterize stacking and unstacking processes and intermediate states in atomic detail. Standard three-point rigid body water force field models lead to significantly accelerated dynamics and an underestimation of enthalpic and entropic contributions. The fully flexible SPCFW water model yielded close agreement with the experimental equilibrium constant, entropy contribution, and, importantly, kinetic observables. In addition, the performance of several other water models was systematically tested in stacking dimerization simulations indicating that the realistic prediction of thermodynamics and kinetics will likely benefit from the use of flexible water models.