Séminaire 09.02.2015 – 11h00

Publié le : 09/02/2015

Miha Kastelic (Université de Ljubljana) présentera un séminaire le 9 février à 11h dans la bibliothèque du laboratoire PHENIX (7e étage, bâtiment F, porte 754) intitulé :

The mechanism of protein aggregation in salt solutions


Aggregation of proteins is a characteristic of amyloid diseases such as Alzheimer’s and Parkinson’s and a major obstacle in formulating biologic drugs, so better understanding of this process is of great importance. Atomistic– level molecular simulations are not practical for studying multi–protein interactions in solutions that are complicated mixture of salts as well as other ligands, excipients, etc. So, a traditional approach is to adapt colloid theories, such as the Deryaguin–Landau–Verwey–Overbeek [1] theory. However, “the isotropic models (such as DLVO) fail to describe the phase diagram of protein solutions quantitatively and cannot address phenomena such as protein aggregation and self- assembly” [2, 3]. Such models typically yield coexistence curves that are too narrow and/or overestimating the critical temperature of the phase diagram.

Coarse–grained statistical mechanics can be useful for protein solutions, but it needs to go beyond central–force (isotropic) approximations. In addition, to obtain the correct shape of the coexistence curves, the protein–protein interactions have to be of short range [4]. Here, we develop a simple theoretical model for protein–protein aggregation in salt solutions. We picture proteins as spheres having M square–well–energy “binding sites” on the surface. We treat this model through Wertheim’s thermodynamic perturbation theory [5]. The depth and range of the potential well, giving accurate liquid–liquid coexistence curves for lysozyme and γIIIa–crystallin solutions in respective buffers, are in the range of the hydrogen bond values. The calculation also provides good fits to the cloud–point curves of lysozyme as a function of the types and concentrations of the salt, added to the buffer at constant total ionic strength. It then predicts second virial coefficients and full coexistence curves vs. added salt type and concentration without further experiments.

[1] Verwey EJ, Overbeek JTG (1948) Theory of the stability of lyophobic colloids (Elsevier).

[2] Lomakin A, Asherie N, Benedek GB (1999) Aeolotopic interactions of globular proteins. Proc Natl Acad Sci USA 96:9465-9468.

[3] Lomakin A, Asherie N, Benedek GB (1996) Monte Carlo study of phase separation in aqueous protein solutions. J Chem Phys 104:1646-1656.

[4] tenWolde RR, Frenkel D (1997) Enhancement of protein crystal nucleation by critical density fluctuations. Science 277:1975-1978.

[5] Chapman WG, Jackson G, Gubbins K (1988) Phase equilibria of associating fluids chain molecules with multiple bonding sites. Mol Phys 65:1057-1079.