Electronic Properties of Protein Destabilizers and Stabilizers: Implications for Preferential Binding and Exclusion Mechanisms.

We study the electronic properties of low-weight organic co-solutes by means of conceptual density functional theory calculations. Our results highlight the important role of certain chemical reactivity descriptors such as chemical hardness, electronegativity, nucleofugality, and the electrofugality as important criteria to classify protein stabilizers and destabilizers. Our results imply Lewis basic properties with lower chemical hardness for stabilizers, while destabilizers show higher Lewis acidity with higher chemical hardness. Further consideration of analytical calculations in terms of transfer energies reveals the crucial role of co-solute-protein interactions which significantly change the interaction pattern of the stabilizing or destabilizing species. The corresponding outcomes connect statistical thermodynamics with the electronic properties of co-solutes and also allow us to define general principles for strong stabilizers and destabilizers.