Essential Role of Hydration in Aggregation of Misfolded Prion Proteins: Quantification by Molecular Theory of Solvation

Abstract

A statistical-mechanical, three-dimensional molecular theory of solvation (also know as 3D-RISM) and molecular mechanics were used to study the thermodynamics of aggregation of misfolded prion proteins, based on the theoretical molecular models proposed so far. These include the β-helical prion trimer (BPT) model of Govaerts et al. (2004), the domain-swapped trimeric prion (DSTP) model of Yang et al. (2005), and the model built after the spiral model of DeMarco and Daggett (2004). It is shown that the solvation contribution to the association free energy can overcome the gain in the internal energy upon association of the proteins. The solvation entropic contribution is as important as the energetic term in the total association free energy. Our calculations show that the spiral-like model is thermodynamically less stable, compared to the DSTP and BPT models. Among the latter two models, the DSTP model is more favorable to association. Quantitative assessment of the solvation effects on the association thermodynamics of prion proteins is provided, and explicitly shows that the solvation contribution is a driving force of the association, in particular, for the existing theoretical models of misfolded prion proteins.

Acknowledgements

We acknowledge financial support by the Alberta Prion Research Institute (APRI) and the National Research Council (NRC) of Canada. The computations were supported by the Centre of Excellence in Integrated Nanotools at the University of Alberta. The protein figures were produced with the visualization program VMD (Humphrey et al., 1996). We are grateful to Dr. Cédric Govaerts and Dr. Holger Wille for providing the structure of the BPT model, and to Dr. Daniel L. Cox for providing the structure of the DSTP model.