Universal effects of solvent species on the stabilized structure of a protein

TL;DR

This study examines how different solvents influence protein stability, revealing that energetic and entropic factors dominate in different environments, with implications for understanding protein folding.

Contribution

It introduces a minimal computational approach to predict solvent effects on protein stability, applicable across various proteins and solvents, aligning well with experimental data.

Findings

Energetic dominance in methanol, ethanol, and cyclohexane stabilizes alpha-helices.

Entropic effects in water promote side-chain packing and secondary structure balance.

Method provides consistent predictions with experimental observations.

Abstract

We investigate the effects of solvent specificities on the stability of the native structure (NS) of a protein on the basis of our free-energy function (FEF). We use CPB-bromodomain (CBP-BD) and apoplastocyanin (apoPC) as representatives of the protein universe and water, methanol, ethanol, and cyclohexane as solvents. The NSs of CBP-BD and apoPC consist of 66$\%$ $\alpha$-helices and of 35$\%$ $\beta$-sheets and 4$\%$ $\alpha$-helices, respectively. In order to assess the structural stability of a given protein immersed in each solvent, we contrast the FEF of its NS against that of a number of artificially created, misfolded decoys possessing the same amino-acid sequence but significantly different topology and $\alpha$-helix and $\beta$-sheet contents. We find that for both CBP-BD and apoPC, the energetic component dominates in methanol, ethanol, and cyclohexane, with the most stable structures in these solvents sharing the same characteristics described as an association of a-helices. In water, the entropic component is as strong as or even stronger than the energetic one, with a large gain of translational, configurational entropy of water becoming crucially important, so that the relative contents of $\alpha$-helix and $\beta$-sheet and the content of total secondary structures are carefully selected to achieve sufficiently close packing of side chains. Our analysis, which requires minimal computational effort, can be applied to any protein immersed in any solvent and provides robust predictions that are quite consistent with the experimental observations for proteins in different solvent environments, thus paving the way toward a more detailed understanding of the folding process.