Density Functional Theory for Protein Transfer Free Energy

• Published in: The journal of physical chemistry. B Vol. 117; no. 42; pp. 13278 - 13290
• Main Authors: Mills, Eric A, Plotkin, Steven S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 24.10.2013
• Subjects: Backbone; Biological and medical sciences; Chains (polymeric); Density functional theory; Depletion; Entropy; Formalism; Free energy; Fundamental and applied biological sciences. Psychology; Methylamines - chemistry; Models, Molecular; Molecular biophysics; Physical chemistry in biology; Proteins; Proteins - chemistry; Proteins - metabolism; Solvents; Solvents - chemistry; Surface Properties; Temperature; Solvent effect; Density functional method; Interaction potential; Free energy; Protein
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp403600q

We cast the problem of protein transfer free energy within the formalism of density functional theory (DFT), treating the protein as a source of external potential that acts upon the solvent. Solvent excluded volume, solvent-accessible surface area, and temperature dependence of the transfer free energy all emerge naturally within this formalism, and may be compared with simplified “back of the envelope” models, which are also developed here. Depletion contributions to osmolyte induced stability range from 5 to 10k B T for typical protein lengths. The general DFT transfer theory developed here may be simplified to reproduce a Langmuir isotherm condensation mechanism on the protein surface in the limits of short-ranged interactions, and dilute solute. Extending the equation of state to higher solute densities results in non-monotonic behavior of the free energy driving protein or polymer collapse. Effective interaction potentials between protein backbone or side chains and TMAO are obtained, assuming a simple backbone/side chain two-bead model for the protein with an effective 6–12 potential with the osmolyte. The transfer free energy δg shows significant entropy: d(δg)/dT ≈ 20k B for a 100-residue protein. The application of DFT to effective solvent forces for use in implicit-solvent molecular dynamics is also developed. The simplest DFT expressions for implicit-solvent forces contain both depletion interactions and an “impeded-solvation” repulsive force at larger distances.