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.