Ionic liquids (ILs) are versatile solvents for a broad range of biotechnological applications. Recent experimental and simulation results highlight the potential benefits of dilute ILs in aqueous solution (aqueous ILs) in order to modify protein and DNA structures systematically. In contrast to a limited number of standard co-solutes like urea, ectoine, trimethylamine-N-oxide (TMAO), or guanidinium chloride, the large amount of possible cation and anion combinations in aqueous ILs can be used to develop tailor-made stabilizers or destabilizers for specific purposes. In this review article, we highlight common principles and differences between aqueous ILs and standard co-solutes with a specific focus on their underlying macromolecular stabilization or destabilization behavior. In combination with statistical thermodynamics theories, we present an efficient framework, which is used to classify structure modification effects consistently. The crucial importance of enthalpic and entropic contributions to the free energy change upon IL-assisted macromolecular unfolding in combination with a complex destabilization mechanism is described in detail. A special focus is also set on aqueous IL-DNA interactions, for which experimental and simulation outcomes are summarized and discussed in the context of previous findings.

We study ectoine-induced destabilization effects on DNA hairpins by a combination of atomistic molecular dynamics simulations, experiments, and theoretical approaches.

Trimethylamine-N-oxide (TMAO) and urea are commonly produced in many extremophilic microorganisms that live in harsh environments. In view of high temperature, high pressure, or high salt content, TMAO is known as a protein structure stabilizer, whereas urea destabilizes protein structures even under ambient conditions. Despite clear evidence, destabilizers are often regarded as chaotropes, meaning water-structure breakers, whereas kosmotropes as water-structure makers are classified as stabilizers. Using atomistic molecular dynamics simulations, we study aqueous mixtures of TMAO and urea in various biologically relevant concentrations to gain insight into the molecular details of their mutual cross-interactions and their influence on water dynamics and structure. Our results for binary and ternary solutions in combination with different mixing ratios show that both co-solutes strengthen the water network in terms of dynamic and structural aspects. Slight differences in the water binding behavior between both species result in only negligible compensation effects. The outcomes of our simulations thus question the validity and the ill-considered use of attributes like kosmotropic or chaotropic substances for stabilizers and destabilizers.

In nature, a wide range of biological processes such as transcription termination and intermolecular binding depend on the formation of specific DNA secondary and tertiary structures. These structures can be both stabilized or destabilized by different cosolutes coexisting with nucleic acids in the cellular environment. In our molecular dynamics simulation study, we investigate the binding of urea at different concentrations to short 7-nucleotide single-stranded DNA structures in aqueous solution. The local concentration of urea around a native DNA hairpin in comparison to an unfolded DNA conformation is analyzed by a preferential binding model in light of the Kirkwood-Buff theory. All our findings indicate a pronounced accumulation of urea around DNA that is driven by a combination of electrostatic and dispersion interactions and accomplished by a significant replacement of hydrating water molecules. The outcomes of our study can be regarded as a first step into a deeper mechanistic understanding toward cosolute-induced effects on nucleotide structures in general.