Solvent Quality and Nonbiological Oligomer Folding: Revisiting Conventional Paradigms

TL;DR

This study uses molecular dynamics simulations to explore how solvent type influences the folding stability of a nonbiological oligomer, revealing that electrostatics dominate folding behavior regardless of solvent, challenging traditional solvent quality paradigms.

Contribution

The paper provides a detailed atomistic analysis of oligomer folding in different solvents, emphasizing electrostatics over hydrogen bonding and highlighting the complex role of entropy-enthalpy compensation.

Findings

Folding stability varies significantly across solvents: stable in water, marginal in n-hexane, unstable in cyclohexane.

Hydrogen bonds with water do not influence folding, indicating electrostatics are the main driving force.

Entropy-enthalpy compensation explains differences in stability among similar solvents.

Abstract

We report on extensive molecular dynamics atomistic simulations of a \textit{meta}-substituted \textit{poly}-phenylacetylene (pPA) foldamer dispersed in three solvents, water \ce{H2O}, cyclohexane \ce{cC6H12}, and \textit{n}-hexane \ce{nC6H14}, and for three oligomer lengths \textit{12mer}, \textit{16mer} and \textit{20mer}. At room temperature, we find a tendency of the pPA foldamer to collapse into a helical structure in all three solvents but with rather different stability character, stable in water, marginally stable in n-hexane, unstable in cyclohexane. In the case of water, the initial and final number of hydrogen bonds of the foldamer with water molecules is found to be unchanged, with no formation of intrachain hydrogen bonding, thus indicating that hydrogen bonding plays no role in the folding process. In all three solvents, the folding is found to be mainly driven by electrostatics, nearly identical in the three cases, and largely dominant compared to van der Waals interactions that are different in the three cases. This scenario is also supported by the analysis of distribution of the bond and dihedral angles and by a direct calculation of the solvation and transfer free energies via thermodynamic integration. The different stability in the case of cyclohexane and n-hexane notwithstanding their rather similar chemical composition can be traced back to the different entropy-enthalpy compensation that is found similar for water and n-hexane, and very different for cyclohexane. A comparison with the same properties for \textit{poly}-phenylalanine oligomers underscores the crucial differences between pPA and peptides. To highlight how these findings can hardly be interpreted in terms of a simple "good" and "poor" solvent picture, a molecular dynamics study of a bead-spring polymer chain in a Lennard-Jones fluid is also included.