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Prion and water: tight and dynamical hydration sites have a key role in structural stability.

ABSTRACT: The propensity to form fibril in disease-related proteins is a widely studied phenomenon, but its correlation, if any, with structural characteristics of the associated proteins is not clearly understood. However, the observation has been made that some proteins that readily form amyloid have a significant number of backbone H bonds that are exposed to solvent molecules, suggesting that these regions have a propensity toward protein interaction and aggregation [Fernandez, A. & Scheraga, H. A. (2003) Proc. Natl. Acad. Sci. USA 100, 113-118]. High-resolution x-ray structures of the sheep and human C-terminal prion protein have provided a useful description of surface and partially buried waters. By molecular dynamics simulations, we investigated the structural role of these water molecules. The solvent dynamical behavior on the protein surface reveals significant features about the stability and the potential interactions of the prion protein. The protein presents regions of tightly bound conserved waters that are necessary to hold in place local elements of the fold, as well as regions where the local water is in fast exchange with bulk water. These results are evidenced by a map of the spatial distribution entropy of the solvent around the protein. The particular behavior of the solvent around these regions may be crucial in the folding stability and in terms of aggregation loci.

SUBMITTER: De Simone A

PROVIDER: S-EPMC1140432 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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Prion and water: tight and dynamical hydration sites have a key role in structural stability.

De Simone Alfonso A Dodson Guy G GG Verma Chandra S CS Zagari Adriana A Fraternali Franca F

Proceedings of the National Academy of Sciences of the United States of America 20050513 21

The propensity to form fibril in disease-related proteins is a widely studied phenomenon, but its correlation, if any, with structural characteristics of the associated proteins is not clearly understood. However, the observation has been made that some proteins that readily form amyloid have a significant number of backbone H bonds that are exposed to solvent molecules, suggesting that these regions have a propensity toward protein interaction and aggregation [Fernandez, A. & Scheraga, H. A. (2 ...[more]

PMID: 15894615

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Project description:We perform path-integral molecular dynamics (PIMD) simulations of H2O and D2O using the q-TIP4P/F model. Simulations are performed at P = 1 bar and over a wide range of temperatures that include the equilibrium (T≥ 273 K) and supercooled (210 ≤T < 273 K) liquid states of water. The densities of both H2O and D2O calculated from PIMD simulations are in excellent agreement with experiments in the equilibrium and supercooled regimes. We also evaluate important thermodynamic response functions, specifically, the thermal expansion coefficient αP(T), isothermal compressibility κT(T), isobaric heat capacity CP(T), and static dielectric constant ε(T). While these properties are in excellent [αP(T) and κT(T)] or semi-quantitative agreement [CP(T) and ε(T)] with experiments in the equilibrium regime, they are increasingly underestimated upon further cooling. It follows that the inclusion of nuclear quantum effects in PIMD simulations of (q-TIP4P/F) water is not sufficient to reproduce the anomalous large fluctuations in density, entropy, and electric dipole moment characteristic of supercooled water. It has been hypothesized that water may exhibit a liquid-liquid critical point (LLCP) in the supercooled regime at P > 1 bar and that such a LLCP generates a maximum in CP(T) and κT(T) at 1 bar. Consistent with this hypothesis and in particular, with experiments, we find a maximum in the κT(T) of q-TIP4P/F light and heavy water at T≈ 230-235 K. No maximum in CP(T) could be detected down to T≥ 210 K. We also calculate the diffusion coefficient D(T) of H2O and D2O using the ring-polymer molecular dynamics (RPMD) technique and find that computer simulations are in remarkable good agreement with experiments at all temperatures studied. The results from RPMD/PIMD simulations are also compared with the corresponding results obtained from classical MD simulations of q-TIP4P/F water where atoms are represented by single interacting sites. Surprisingly, we find minor differences in most of the properties studied, with CP(T), D(T), and structural properties being the only (expected) exceptions.

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Prion and water: tight and dynamical hydration sites have a key role in structural stability.

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Prion and water: tight and dynamical hydration sites have a key role in structural stability.

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