The pH responding proteins

The changes in the environment acidity may lead to important protein conformational changes, even unfolding. Accounting for this effect in silico is a real challenge. A recent paper from the group of D. Baker shows how by modelling the distribution of histidine residues in the network of hydrogen bonds that stabilises the fold of a protein is possible to control the response of a protein to pH changes. The paper is out in the Science magazine here. The possibility to account in simulations for pH has inspired also several computational approaches along the years. Very recently titration method combined to coarse-grained MD simulations was demonstrated to be a cheap but effective strategy in both the simulation of RNA [see Pasquali et al, Interface Focus, 2019, here] and proteins [see Barroso et al, JCTC, 2019, here].

Alzheimer’s disease, an eXtreme problem!

According to the amyloid's cascade hypothesis the wrong cut of the Ab protein and its aggregation into ordered fibrils is at the origin of the Alzheimer’s disease. Following this aggregation process with microscopic details is far to be possible experimentally. However, in silico modelling can help. Recently we have started working on a multi-scale simulation scheme to challenge the problem, and we could follow the aggregation of a simple but insightful amyloid peptide, the Ab(16-22), into prefibrillar states. You can enjoy the details here.  However, too much focus on the aggregation of Ab seems to be the wrong thing to do. In fact, it is a news of recent days that another potential drug intended to remove Ab plaques from the brain of Alzheimer's  affected patients just does not work, and the clinical trial was stopped, read more here. This news failure questions the amyloid cascade, or just indicates that when the symptoms are visible, treating Ab plaques is just to late, some interesting points are debated here.

The fifth sense of a protein: Quinary interactions in SOD1

The interior of living cells is an eXtremely crowded environment, with a large part of the volume being occupied by diverse macromolecules. For a protein it is like to move in a suburban train at rush hour! However, how this crowding affects the life of a protein, in particular its stability, is still unknown. The group of our collaborator (S. Ebbinghaus at the TU in Braunschweig, Germany) using rapid laser-induced temperature jumps, showed that weak transient interactions with the surrounding macromolecules, often referred to as quinary interactions (aka the fifth order of structural organization of a protein), can indeed amplify and even reverse the stability response of proteins to single-point mutations. By performing innovative multi-scale molecular simulations we shed light on the microscopic origin of those interactions, providing a possible explanation of the experimentally observed stability effects. Together, the results highlight the importance of considering weak transient interactions with the intracellular environment when investigating the relationship between stability and function in vivo as well as possible pathogenic misfolding and aggregation paths. The work is published in JACS, see here.

The force, the heat and the shear. Three weaknesses for three perturbations!

Shear unfolding chapter two. Same question: Can proteins unfold in shearing fluid flows, and to what extent? How do the tensile forces exerted by the solvent affect the protein compared to other types of external perturbations such as thermal denaturation, or directional pulling forces used in optic/magnetic tweezers or atomic force microscopy (AFM) experiments? Before the answer: conventional all-atom molecular dynamics simulations often require too much computational effort, hence, we have developed an original methodology using Lattice Boltzmann Molecular Dynamics (LBMD) and the Optimized Potential for Efficient peptide folding Prediction (OPEP) coarse-grained model to inquire the unfolding features of a small Cold Shock Protein subjected to three different perturbations: shear flow, heat shock and pulling force. Since the implicit-solvent OPEP model inherently lacks hydrodynamics, the Lattice Boltzmann framework allowed us to realistically simulate the flow interaction with the protein, while retaining good computational efficiency with respect to explicit-solvent approaches. Here the answer: The direct comparison of the unfolding mechanisms evidenced that the three perturbations act on different weaknesses of the protein, and thus lead on average to very different unfolding pathways. Funny enough, for this small globular protein shear flow acts more similarly to thermal excitation then a direct mechanical force. Our results suggest that the interpretation of experimental studies that rely on force-spectroscopy techniques to investigate natural shear-activated systems, such as the von Willebrand factor or the bacterial adhesin FimH, is not straightforward. The paper is out here.

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.

Mechanics of thermal adaptation

Somero’s corresponding state principle relates protein enhanced thermal stability with mechanical rigidity. A natural way to test the mechanical stiffness of a protein is to apply a directional force as in single molecule AFM experiments. Recent experiments have been therefore inspired by the possible correlation among the mechanical and thermal stabilities. Unfortunately single molecule experiments lack molecular resolution, and in silico realisation of thermal and mechanical unfolding can provide very useful insights. This is exactly what we have done in a recent work focused on two homologues belonging to the Cold Shock Protein family. Our results show that for these species there is not a correlation among the thermal resistance of the thermophilic Csp and its mechanical stability. The paper is out in JPC Letter [here].