Entropic stabilization plays a key role in the non-uniform distribution of oxygen ions and vacancy defects in gadolinium-doped ceria

A new theory describing oxygen ion movement and distribution in YSZ and GDC shows that entropic effects are significant.

All atom insights into the impact of crowded environments on protein stability by NMR spectroscopy

The high density of macromolecules affecting proteins due to volume exclusion has been discussed in theory but numerous in vivo experiments cannot be sufficiently understood taking only pure entropic stabilization into account. Here, we show that the thermodynamic stability of a beta barrel protein increases equally at all atomic levels comparing crowded environments with dilute conditions by applying multidimensional high-resolution NMR spectroscopy in a systematic manner. Different crowding agents evoke a pure stabilization cooperatively and do not disturb the surface or integrity of the protein fold. The here developed methodology provides a solid base that can be easily expanded to incorporate e.g. binding partners to recognize functional consequences of crowded conditions. Our results are relevant to research projects targeting soluble proteins in vivo as it can be anticipated that their thermodynamic stability increase comparably and has consequently to be taken into account to coherently understand intracellular processes.

Water-mediated interactions determine helix formation of peptides in open nanotubes

Water-mediated interactions (WMIs) play diverse roles in molecular biology. They are particularly relevant in geometrically confined spaces such as the interior of the chaperonin, at the interface between ligands and their binding partners, and in the ribosome tunnel. Inspired in part by the geometry of the ribosome tunnel, we consider confinement effects on the stability of peptides. We describe results from replica exchange molecular dynamics simulations of a system containing a 23-alanine or 23-serine polypeptide confined to non-polar and polar nanotubes in the gas phase and when open to a water reservoir. We quantify the effect of water in determining the preferred conformational states of these polypeptides by calculating the difference in the solvation free energy for the helix and coil states in the open nanotube in the two phases. Our simulations reveal several possibilities. We find that nanoscopic confinement preferentially stabilizes the helical state of polypeptides with hydrophobic side chains, which is explained by the entropic stabilization mechanism proposed on the basis of polymer physics. Polypeptide chains with hydrophilic side chains can adopt helical structures within nanotubes, but helix formation is sensitive to the nature of the nanotube due to WMIs. We elaborate on the potential implications of our findings to the stability of peptides in the ribosome tunnel.

Understanding the formation of apremilast cocrystals

Apremilast (APR), an anti-psoriatic agent, easily forms isostructural cocrystals and solvates with aromatic entities, often disobeying at the same time Kitaigorodsky's rule as to the saturation of possible hydrogen-bonding sites. In this paper the reasons for this peculiar behavior are investigated, employing a joint experimental and theoretical approach. This includes the design of cocrystals with coformers having a high propensity towards the formation of both aromatic–aromatic and hydrogen-bonding interactions, determination of their structure, using solid-state NMR spectroscopy and X-ray crystallography, as well as calculations of stabilization energies of formation of the obtained cocrystals, followed by crystal structure prediction calculations and solubility measurements. The findings indicate that the stabilization energies of cocrystal formation are positive in all cases, which results from strain in the APR conformation in these crystal forms. On the other hand, solubility measurements show that the Gibbs free energy of formation of the apremilast:picolinamide cocrystal is negative, suggesting that the formation of the studied cocrystals is entropy driven. This entropic stabilization is associated with the disorder observed in almost all known cocrystals and solvates of APR.

Entropic Stabilization of Cas4 Protein SSO0001 Predicted with Popcoen

Popcoen is a method for configurational entropy estimation of proteins based on machine-learning. Entropy is predicted with an artificial neural network which was trained on simulation trajectories of a large set of representative proteins. Popcoen is extremely fast compared to other approaches based on the sampling of a multitude of microstates. Consequently, Popcoen can be incorporated into a large class of protein software which currently neglects configurational entropy for performance reasons. Here, we apply Popcoen to various conformations of the Cas4 protein SSO0001 of Sulfolobus solfataricus, a protein that assembles to a decamer of known toroidal shape. We provide numerical evidence that the native state (NAT) of a SSO0001 monomer has a similar structure to the protomers of the oligomer, where NAT of the monomer is stabilized mainly entropically. Due to its large amount of configurational entropy, NAT has lower free energy than alternative conformations of very low enthalpy and solvation free-energy. Hence, SSO0001 serves as an example case where neglecting configurational entropy leads to incorrect conclusion. Our results imply that no refolding of the subunits is required during oligomerization which suggests that configurational entropy is employed by nature to largely enhance the rate of assembly.