On the Nature of Guest Complexation in Water: Triggered Wetting-Water-Mediated Binding.

The complexity of macromolecular surfaces means that there are still many open questions regarding how specific areas are solvated and how this might affect the complexation of guests. Contributing to the identification and classification of the different possible mechanisms of complexation events in aqueous solution, and as part of the recent SAMPL8 exercise, we report here on the synthesis and conformational properties of TEEtOA 2, a cavitand with conformationally flexible ethyl groups at its portal. Using a combination of ITC and NMR spectroscopy, we report the binding affinities of a series of carboxylates to 2 and compare it to a related cavitand TEMOA 1. Additionally, we report MD simulations revealing how the wetting of the pocket of 2 is controlled by the conformation of its rim ethyl groups and, correspondingly, a novel triggered wetting, guest complexation mechanism, whereby the approaching guest opens up the pocket of the host, inducing its wetting and ultimately allows the formation of a hydrated host-guest complex (H·G·H2O). A general classification of complexation mechanisms is also suggested.

Anti-epileptic drug topiramate upregulates TGFß1 and SOX9 expression in primary embryonic palatal mesenchyme cells: Implications for teratogenicity.

Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFß1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFß1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFß1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFß1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.

Proximal charge effects on guest binding to a non-polar pocket.

Science still does not have the ability to accurately predict the affinity that ligands have for proteins. In an attempt to address this, the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) series of blind predictive challenges is a community-wide exercise aimed at advancing computational techniques as standard predictive tools in rational drug design. In each cycle, a range of biologically relevant systems of different levels of complexity are selected to test the latest modeling methods. As part of this on-going exercise, and as a step towards understanding the important factors in context dependent guest binding, we challenged the computational community to determine the affinity of a series of negatively and positively charged guests to two constitutionally isomeric cavitand hosts: octa-acid 1, and exo-octa acid 2. Our affinity determinations, combined with molecular dynamics simulations, reveal asymmetries in affinities between host-guest pairs that cannot alone be explained by simple coulombic interactions, but also point to the importance of host-water interactions. Our work reveals the key facets of molecular recognition in water, emphasizes where improvements need to be made in modelling, and shed light on the complex problem of ligand-protein binding in the aqueous realm.

Thermal properties and surface chemistry of cotton varieties mineralized with calcium carbonate polymorphs by cyclic dipping.

In this study, hydroentangled cotton nonwovens were identified as effective hosts for mineralization of calcium carbonate (CaCO3) polymorphs to modify and improve their properties. All cotton varieties studied, including raw white cotton, scoured white cotton, and raw brown cotton, readily crystallized CaCO3 via a simple cyclic dipping process. A combination of analyses agreed that the surface chemistry of cotton fibers influenced the formation of different CaCO3 polymorphs. Scoured white cotton that consisted of almost pure cellulose predominantly produced the most stable calcite, whereas raw white and raw brown cottons that contain proteins facilitated the production of partial metastable vaterite. The morphology of calcite was better defined on the scoured cotton. The mineralization altered the hydrophobic surface of raw cottons to be hydrophilic, i.e., two-fold increase in moisture regain and decrease in water contact angle from 130 to 0 degrees. The mineralized cottons also exhibited improved thermal resistance, i.e., slower thermal decomposition with decreased activation energies and reduction in heat release capacity by up to 40%.