Analytical model for studying how environmental factors influence protein conformational stability in solution

Abstract

We introduce an analytical modeling strategy for probing the conformational stability of globular proteins in aqueous solution. In this approach, the intrinsic (i.e., infinite dilution) thermodynamic stability and coarse structural properties of the proteins, as well as the effective protein-protein interactions, derive from a heteropolymer collapse theory that incorporates predicted temperature- and pressure-dependent hydrophobic interactions. Protein concentration effects are estimated by integrating this information into a molecular thermodynamic model, which is an ad hoc generalization of the exact equilibrium theory of a one-dimensional binary mixture of square-well particles that interconvert through an isomerization (i.e., folding) reaction. The end result is an analytical multiscale modeling approach which, although still schematic, can predict that folded proteins exhibit a closed-loop region of stability in the pressure-temperature plane and that protein concentration has a nonmonotonic effect on protein stability, results consistent with qualitative trends observed in both experiments of protein solutions and simulations of coarse-grained protein models.