When solvent breaks a protein: protein unfolding under shear

Proteins break under the action of different perturbations, the temperature, chemicals, mechanical forces. Fluid flow too, in special condition, unfolds a protein. In some biological processes, the fluid induced perturbation is even functional. That is the case of blood coagulation where the long chain of the von Willibrend factor unrolls and extends under the action of blood shear flow caused by a vessel injury. Other proteins, known as catch-bonds, use the tensile force to strength the binding with their substrate via a sort of allosteric conformational change. It is therefore intriguing to understand in which conditions a protein unfolds in shear flow, and the molecular mechanism of the process. We have dedicated a recent paper to this by exploiting the power of the lattice Boltzmann MD technique. Surf it here.

Solvent disorder and protein dynamical transition

Protein dynamical transition (PDT) indicates the sudden activation of protein fluctuations above a critical temperature, Td ~ 220-240 K. The phenomenon has attracted the attention of scientists along the years because the possible implications. First, it has been strongly related to the role of the solvent environment surrounding the protein, and namely its physical changes. It is not surprising that many concepts coined in the community of liquids were transposed to scratch insights on the problem. Secondly, this problem represented the door through which the community active in neutron scattering entered heavily in the discussion about protein dynamics and function. Yet today, numerous  interesting works focusing on the protein dynamical transition appear in top-notch magazines, see e.g. Weik and coworkers discussed the correlation among water translation and protein fluctuation across the PDT [here] while Hong and coworkers claim that the transition is an intrinsic feature of the dry protein energy landscape [here]. We are participating to the debate, as presented in the post dedicated to Lindemann criterion. To better understand the relationship among protein motion and solvent behaviour, we have recently developed a methodology that using data from particle based simulations, can fruitfully estimate the change in the water  hydrogen bond connectivity, in space, in time, and in temperature. We show the PDT correlates to the sudden increase in the configurational disorder of the water HB network enveloping the proteins. Our finding links, in the spirit of the Adam–Gibbs relationship, the diffusivity of protein atoms, as quantified by the hydrogen mean-square displacements, and the thermodynamic solvent configurational entropy. Enjoy the paper here, and a comment in the P. Ball's blog Water in Biology.

Protein melting: the Lindemann criterion applied to proteins

The full knowledge of the structural and dynamic properties of the native, transition, intermediate, and denatured states of proteins is a key goal of life and physical sciences. Indeed, this kind of information can lay the foundation for the deep understanding of folding and unfolding of proteins which, in turn, are crucial processes in the metabolism of cells, regulating biological activity and targeting proteins to different cellular locations. In our work (Katava et. al., PNAS (2017) here)we focus the attention on the sub-nanosecond dynamics of a model protein in correspondence of the melting transition, when it is embedded in three different solvents. We show that, although the different solvents modify the protein melting temperature, a common scaling toward a constant value for the local fluctuations is attained when approaching the unfolding temperature.
Quite remarkably, this result is reminiscent of the famous criterion for melting of solids proposed by F.A. Lindemann in 1910, which states that crystals liquefy when their atomic root mean square fluctuations exceed a certain threshold value. The common scaling we found for protein mean square displacements at melting not only sheds unique light on the relationship between protein flexibility and stability, but also opens the possibility to predict protein unfolding in special environments (e.g., the cell interior) by following thermal local fluctuations.
The striking analogy between the melting of inorganic crystals and native biomolecules suggests that these seemingly very different systems may share similar behavior in correspondence of phase transitions. On these grounds, we may speculate that simplified theories of solids can also be effectively applied to interpret the behavior of complex biological systems.

Stay wet, stay stable?

Proteins often host water molecules inside buried cavities or superficial clefts. The presence of these molecules was first resolved via x-ray crystallography and their exchanging dynamics with the external solution was deeply investigated by NMR experiments, the interested readers can dig all the work done by B. Halle and collaborators, see the Halle's web page. Molecular Dynamics simulations also shed light on the molecular mechanisms of this exchange, earlier work by Hummer and Garcia [1] and Sterpone, Ceccarelli and Marchi [2], date back to 2000 or so. It was always questioned the contribution of this set of molecules to the stability of the protein fold. Very recently we decided to tackle the problem and relate it to the issue of protein thermal stability [3]. The starting question was: is the extra stability of a thermophilic protein correlated to its internal hydration. For our study case, the pair of homologous G-domain from the mesophilic E. coli and the hyperthermophilic S. solfataricus, the answer is yes, at least a bit. The manuscript is here.

[1] G. Hummer and A.E. Garcia "Water Penetration and Escape in Proteins". Proteins 2000, 38, 261−272.
[2] F. Sterpone, M. Ceccarelli, M. Marchi, "Dynamics of Hydration in Hen Egg White Lysozyme. J. Mol. Biol. 2001, 311, 409−419.
[3] O. Rahaman, M. Kalimeri, S. Melchionna, J. Henin, F. Sterpone "Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains ", J. Phys. Chem. B 2014 in press.