Progressive dry-core-wet-rim hydration trend in a nested-ring topology of protein binding interfaces

<p>Abstract</p> <p>Background</p> <p>Water is an integral part of protein complexes. It shapes protein binding sites by filling cavities and it bridges local contacts by hydrogen bonds. However, water molecules are usually not included in protein interface models in the past, and few distribution profiles of water molecules in protein binding interfaces are known.</p> <p>Results</p> <p>In this work, we use a tripartite protein-water-protein interface model and a nested-ring atom re-organization method to detect hydration trends and patterns from an interface data set which involves immobilized interfacial water molecules. This data set consists of 206 obligate interfaces, 160 non-obligate interfaces, and 522 crystal packing contacts. The two types of biological interfaces are found to be drier than the crystal packing interfaces in our data, agreeable to a hydration pattern reported earlier although the previous definition of immobilized water is pure distance-based. The biological interfaces in our data set are also found to be subject to stronger water exclusion in their formation. To study the overall hydration trend in protein binding interfaces, atoms at the same burial level in each tripartite protein-water-protein interface are organized into a ring. The rings of an interface are then ordered with the core atoms placed at the middle of the structure to form a nested-ring topology. We find that water molecules on the rings of an interface are generally configured in a dry-core-wet-rim pattern with a progressive level-wise solvation towards to the rim of the interface. This solvation trend becomes even sharper when counterexamples are separated.</p> <p>Conclusions</p> <p>Immobilized water molecules are regularly organized in protein binding interfaces and they should be carefully considered in the studies of protein hydration mechanisms.</p

Volume-based solvation models out-perform area-based models in combined studies of wild-type and mutated protein-protein interfaces

<p>Abstract</p> <p>Background</p> <p>Empirical binding models have previously been investigated for the energetics of protein complexation (ΔG models) and for the influence of mutations on complexation (i.e. differences between wild-type and mutant complexes, ΔΔG models). We construct binding models to directly compare these processes, which have generally been studied separately.</p> <p>Results</p> <p>Although reasonable fit models were found for both ΔG and ΔΔG cases, they differ substantially. In a dataset curated for the absence of mainchain rearrangement upon binding, non-polar area burial is a major determinant of ΔG models. However this ΔG model does not fit well to the data for binding differences upon mutation. Burial of non-polar area is weighted down in fitting of ΔΔG models. These calculations were made with no repacking of sidechains upon complexation, and only minimal packing upon mutation. We investigated the consequences of more extensive packing changes with a modified mean-field packing scheme. Rather than emphasising solvent exposure with relatively extended sidechains, rotamers are selected that exhibit maximal packing with protein. This provides solvent accessible areas for proteins that are much closer to those of experimental structures than the more extended sidechain regime. The new packing scheme increases changes in non-polar burial for mutants compared to wild-type proteins, but does not substantially improve agreement between ΔG and ΔΔG binding models.</p> <p>Conclusion</p> <p>We conclude that solvent accessible area, based on modelled mutant structures, is a poor correlate for ΔΔG upon mutation. A simple volume-based, rather than solvent accessibility-based, model is constructed for ΔG and ΔΔG systems. This shows a more consistent behaviour. We discuss the efficacy of volume, as opposed to area, approaches to describe the energetic consequences of mutations at interfaces. This knowledge can be used to develop simple computational screens for binding in comparative modelled interfaces.</p

Visual Genome-Wide RNAi Screening to Identify Human Host Factors Required for Trypanosoma cruzi Infection

The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a neglected tropical infection that affects millions of people in the Americas. Current chemotherapy relies on only two drugs that have limited efficacy and considerable side effects. Therefore, the development of new and more effective drugs is of paramount importance. Although some host cellular factors that play a role in T. cruzi infection have been uncovered, the molecular requirements for intracellular parasite growth and persistence are still not well understood. To further study these host-parasite interactions and identify human host factors required for T. cruzi infection, we performed a genome-wide RNAi screen using cellular microarrays of a printed siRNA library that spanned the whole human genome. The screening was reproduced 6 times and a customized algorithm was used to select as hits those genes whose silencing visually impaired parasite infection. The 162 strongest hits were subjected to a secondary screening and subsequently validated in two different cell lines. Among the fourteen hits confirmed, we recognized some cellular membrane proteins that might function as cell receptors for parasite entry and others that may be related to calcium release triggered by parasites during cell invasion. In addition, two of the hits are related to the TGF-beta signaling pathway, whose inhibition is already known to diminish levels of T. cruzi infection. This study represents a significant step toward unveiling the key molecular requirements for host cell invasion and revealing new potential targets for antiparasitic therapy

Superballistic flow of viscous electron fluid through graphene constrictions

Electron–electron (e–e) collisions can impact transport in a variety of surprising and sometimes counterintuitive ways1,2,3,4,5,6. Despite strong interest, experiments on the subject proved challenging because of the simultaneous presence of different scattering mechanisms that suppress or obscure consequences of e–e scattering7,8,9,10,11. Only recently, sufficiently clean electron systems with transport dominated by e–e collisions have become available, showing behaviour characteristic of highly viscous fluids12,13,14. Here we study electron transport through graphene constrictions and show that their conductance below 150 K increases with increasing temperature, in stark contrast to the metallic character of doped graphene15. Notably, the measured conductance exceeds the maximum conductance possible for free electrons16,17. This anomalous behaviour is attributed to collective movement of interacting electrons, which ‘shields’ individual carriers from momentum loss at sample boundaries18,19. The measurements allow us to identify the conductance contribution arising due to electron viscosity and determine its temperature dependence. Besides fundamental interest, our work shows that viscous effects can facilitate high-mobility transport at elevated temperatures, a potentially useful behaviour for designing graphene-based devices

Influence of Goat Milk on Iron Deficiency Anemia Recovery

Despite Fe deficiency and overload having been widely studied, researchers are still looking for natural foods with beneficial nutritional characteristics which can help to palliate or recover this highly prevalent nutritional deficiency. In this sense, goat milk is a natural food with beneficial nutritional characteristics which can help to reach these goals. Goat milk consumption leads to a better recovery of body Fe stores, minimizing Ca-Fe interactions and improving Fe status and its absorption and increases the Cu bioavailability, an essential mineral for erythropoiesis. In addition, goat milk consumption improves DNA stability, due to the quality its fat, together with the high levels of bioavailable Mg and Zn, even during chronic Fe-overload. Caprine milk also has positive effects on antioxidant defence, even in a situation of Fe overload, limiting lipid peroxidation and improving antioxidant status. Finally improves bone turnover, impaired by Fe-deficiency, increasing bone formation and diminishing parathorme levels. Therefore, inclusion of goat milk is recommended in the diet of people, who suffer nutritional Fe deficiency anemia, since this type of milk helps to relieve the adverse effects produced in bone turnover, oxidative stress and mineral bioavailability due to the Fe deficienc