Transfer Models for Chemical Protein Denaturation

Orateur : Prof. Dominik HORINEK (Universität Regensburg, Germany)

Protein denaturation by urea remained controversial after many decades of research : many results suggest that urea denatures by favorable solvation of both the side chains and the backbone, but the transfer model ascribes the denaturation power exclusively to urea’s interactions with the backbone. On the path towards a complete understanding of the underlying physical-chemical principles, we present insight by molecular simulations in combination with liquid state theories. Peptide stability in concentrated solutions of urea is studied by a combination of interface thermodynamics, Kirkwood-Buff solvation theory, and molecular dynamics simulation results for pure urea/water mixtures and for peptide chains in these solvents. Different residue types and secondary structure motifs of the peptide are studied. The results are used for a rigorous evaluation of different implementations of the transfer model, which reveals that the established implementation gives an unsatisfactory prediction of the scaling of transfer free energies with the solvent accessible area. This scaling is well satisfied after an inconsistency in the treatment of the backbone contribution is corrected. The new implementation works also best in the prediction of experimental m values of a set of 36 proteins. The separation into side chain and backbone contributions shows that they are in average of equal magnitude, which is in agreement with many other studies. Thus, our validations and proposed improvements consolidate the transfer model as a useful tool for the prediction and interpretation of the solvation thermodynamics of proteins in mixed solvents.

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