Multiscale modelling of soft matter is an emerging field that has made rapid progress in the past decade.Several methods for systematic coarse-graining of molecular liquids and soft matter systems have been proposed in recent years. Herein, we review these methods and discuss a selected number of applications as well as limitations of the models and remaining challenges in developing representative and transferable pair potentials.

We propose a physical mechanism for co-nonsolvency of a stimulus-responsive polymer in water/methanol mixed solution based on results obtained with molecular simulations. Even though the phenomenon is well known, the mechanism behind co-nonsolvency is still under debate. Herein, we study co-nonsolvency of poly(N-isopropylacrylamide) (PNiPAM) in methanol aqueous solutions, the most widely studied and experimentally well-characterized system. Our results show that at low alcohol content of the solution methanol preferentially binds to the PNiPAM globule and drives polymer collapse. The energetics of electrostatic, hydrogen bonding, or bridging-type interactions with the globule is found to play no role. Instead, preferential methanol binding results in a significant increase in the globule's configurational entropy, stabilizing methanol-enriched globular structures over wet globular structures in neat water. This mechanism drives the reduction of the lower critical solution temperature with increasing methanol content in the co-nonsolvency regime and eventually leads to polymer collapse. The globule-to-coil re-entrance at high methanol concentrations is instead driven by changes in solvent-excluded volume of the coil and globular states imparted by a decrease in solvent density with increasing methanol content of the solution: with increasing proportion of larger solvent particles (methanol), the entropic (cavity formation) cost of redistributing solvent molecules upon polymer re-entrance becomes smaller. This effect provides a natural explanation for the experimentally observed dependence of the re-entrance transition on chain molecular weight.

Protective osmolytes are chemical compounds that shift the protein folding/unfolding equilibrium toward the folded state under osmotic stresses. The most widely considered protection mechanism assumes that osmolytes are depleted from the protein's first solvation shell, leading to entropic stabilization of the folded state. However, recent theoretical and experimental studies suggest that protective osmolytes may directly interact with the macromolecule. As an exemplary and experimentally well-characterized system, we herein discuss poly(N-isopropylacrylamide) (PNiPAM) in water whose folding/unfolding equilibrium shifts toward the folded state in the presence of urea. On the basis of molecular dynamics simulations of this specific system, we propose a new microscopic mechanism that explains how direct osmolyte-macromolecule interactions confer stability to folded states. We show that urea molecules preferentially accumulate in the first solvation shell of PNiPAM driven by attractive van der Waals dispersion forces with the hydrophobic isopropyl groups, leading to the formation of low entropy urea clouds. These clouds provide an entropic driving force for folding, resulting in preferential urea binding to the folded state and a decrease of the lower folding temperature in agreement with experiment. The simulations further indicate that thermodynamic nonideality of the bulk solvent opposes this driving force and may lead to denaturation, as illustrated by simulations of PNiPAM in aqueous solutions with dimethylurea. The proposed mechanism provides a new angle on relations between the properties of protecting and denaturing osmolytes, salting-in or salting-out effects, and solvent nonidealities.

We revisit the mechanism for cononsolvency of PNIPAM in water/methanol mixtures. Using extensive molecular dynamics simulations, we calculate the calorimetric enthalpy of the PNIPAM collapse transition and observe a unique fingerprint of PNIPAM cononsolvency which is analyzed in terms of microscopic interactions. We find that polymer hydration is the determining factor for PNIPAM collapse in the cononsolvency regime. In particular, it is shown that methanol frustrates the ability of water to form hydrogen bonds with the amide proton and therefore causes polymer collapse.

Stabilization of macromolecular folded states in solution by protective osmolytes has been traditionally explained on the basis of preferential osmolyte depletion from the macromolecule's first solvation shell. However recent theoretical and experimental studies suggest that protective osmolytes may directly interact with the macromolecule. An example is the stabilization of the collapsed globular state of poly(N-isopropylacrylamide) (PNiPAM) by urea in aqueous solution. Based on Molecular Dynamics simulations we have characterized the mechanism through which urea stabilizes the collapsed state of PNiPAM in water. Analysis and comparison of the different components of the excess chemical potentials of folded and unfolded PNiPAM chains in aqueous urea solutions indicates that enthalpic interactions play no role in stabilizing the collapsed state. We instead find that with increasing urea, solvation of the unfolded state is entropically penalized over solvation of the folded state, thereby shifting the folding equilibrium in favour of the folded state. The unfavourable entropy contribution to the excess chemical potential of unfolded PNiPAM chains results from two urea effects: (1) an increasing cost of cavity formation with increasing urea, (2) larger fluctuations in the energy component corresponding to PNiPAM-(co)solvent attractive interactions. These energy fluctuations are particularly relevant at low urea concentrations (<3 M) and result from attractive polymer-urea van der Waals interactions that drive the formation of "urea clouds" but bias the spatial distribution of urea and water molecules with a corresponding reduction of the entropy. We further find indications that urea increases the entropy of the globular state.