Why Do Elastin-Like Polypeptides Possibly Have Different Solvation Behaviors in Water–Ethanol and Water–Urea Mixtures?

[Image: see text] The solvent quality determines the collapsed or the expanded state of a polymer. For example, a polymer dissolved in a poor solvent collapses, whereas in a good solvent it opens up. While this standard understanding is generally valid, there are examples when a polymer collapses even in a mixture of two good solvents. This phenomenon, commonly known as co-non-solvency, is usually associated with a wide range of synthetic (smart) polymers. Moreover, recent experiments have shown that some biopolymers, such as elastin-like polypeptides (ELPs) that exhibit lower critical solution behavior T(l) in pure water, show co-non-solvency behavior in aqueous ethanol mixtures. In this study, we investigate the phase behavior of elastin-like polypeptides (ELPs) in aqueous binary mixtures using molecular dynamics simulations of all-atom and complementary explicit solvent generic models. The model is parameterized by mapping the solvation free energy obtained from the all-atom simulations onto the generic interaction parameters. For this purpose, we derive segment-based (monomer level) generic parameters for four different peptides, namely proline (P), valine (V), glycine (G), and alanine (A), where the first three constitute the basic building blocks of ELPs. Here, we compare the conformational behavior of two ELP sequences, namely -(VPGGG)- and -(VPGVG)-, in aqueous ethanol and -urea mixtures. Consistent with recent experiments, we find that ELPs show co-non-solvency in aqueous ethanol mixtures. Ethanol molecules have preferential binding with all ELP residues, with an interaction contrast of 6–8 k(B)T, and thus driving the coil-to-globule transition. On the contrary, ELP conformations show a weak variation in aqueous urea mixtures. Our simulations suggest that the glycine residues dictate the overall behavior of ELPs in aqueous urea, where urea molecules have a rather weak preferential binding with glycine as observed from the all atom simulations, i.e., less than k(B)T. This weak interaction dilutes the overall effect of other neighboring residues and thus ELPs exhibit a different conformational behavior in aqueous urea in comparison to aqueous ethanol mixtures. While the validation of the latter findings will require a more detailed experimental investigation, the results presented here may provide a new twist to the present understanding of cosolvent interactions with peptides and proteins.