Computation of protein geometry and its applications: Packing and function prediction

This chapter discusses geometric models of biomolecules and geometric constructs, including the union of ball model, the weigthed Voronoi diagram, the weighted Delaunay triangulation, and the alpha shapes. These geometric constructs enable fast and analytical computaton of shapes of biomoleculres (including features such as voids and pockets) and metric properties (such as area and volume). The algorithms of Delaunay triangulation, computation of voids and pockets, as well volume/area computation are also described. In addition, applications in packing analysis of protein structures and protein function prediction are also discussed.Comment: 32 pages, 9 figure

MGOS: A library for molecular geometry and its operating system

The geometry of atomic arrangement underpins the structural understanding of molecules in many fields. However, no general framework of mathematical/computational theory for the geometry of atomic arrangement exists. Here we present "Molecular Geometry (MG)'' as a theoretical framework accompanied by "MG Operating System (MGOS)'' which consists of callable functions implementing the MG theory. MG allows researchers to model complicated molecular structure problems in terms of elementary yet standard notions of volume, area, etc. and MGOS frees them from the hard and tedious task of developing/implementing geometric algorithms so that they can focus more on their primary research issues. MG facilitates simpler modeling of molecular structure problems; MGOS functions can be conveniently embedded in application programs for the efficient and accurate solution of geometric queries involving atomic arrangements. The use of MGOS in problems involving spherical entities is akin to the use of math libraries in general purpose programming languages in science and engineering. (C) 2019 The Author(s). Published by Elsevier B.V

Evaluation of photografted charged sites within polymer monoliths in capillary columns using contactless conductivity detection

Capacitively coupled contactless conductivity detection (C4D) is presented as a novel and versatile means of visualising discrete zones of charged functional groups grafted onto polymer based monoliths. Monoliths were formed within 100 μm UV transparent fused silica capillaries and photografting methods were subsequently used to graft a charged functional monomer, 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) onto discrete regions of the “generic” monolith using a photomask. Post-modification monolith evaluation involves scanning the C4D detector along the length of the monolith to obtain a profile of the exact spatial location of grafted charged functionalities with millimetre accuracy. The methodology was extended to the visualisation of several zones of immobilised protein (bovine serum albumin) using photografted azlactone groups to enable covalent attachment of the protein to the monolith at precise locations along its length. In addition, the extent of non-specific binding of protein to the ungrafted regions of the monolith due to hydrophobic interactions could be monitored as an increase in background conductivity of the stationary phase. Finally, the technique was cross-validated using fluorescence microscopy by immobilising green fluorescent protein (GFP) in discrete zones and comparing the profiles obtained using both complementary techniques

Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus.

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus

Processing peracetic acid treated bloodmeal into bioplastic

Renewable and biodegradable bioplastics can be produced from biopolymers such as proteins. Animal blood is a by-product from meat processing and is rich in protein. It is dried into low value bloodmeal and is used as animal feed or fertiliser. Previous work has shown that bloodmeal can be converted into a thermoplastic using water, urea, sodium dodecyl sulphate (SDS), sodium sulphite and triethylene glycol (TEG). To increase its range of applications and acceptance from consumers, the colour and odour was removed from bloodmeal using peracetic acid (PAA). The aim of this study was to investigate the bioplastic processing of 3-5% (w/w) PAA treated bloodmeal. 3-5% PAA treated bloodmeal powder was compression moulded using different combinations of water, TEG, glycerol, SDS, sodium sulphite, urea, borax, salt and sodium silicate at concentrations up to 60 parts per hundred bloodmeal (pphBM). Partially consolidated extrudates and fully consolidated compression moulded sheets were obtained using a combination of water, TEG and SDS. 4% PAA treated bloodmeal produced the best compression moulded sheets and extrudates and was chosen for investigating the effects of water, TEG and SDS concentration on consolidation, specific mechanical energy input (SME) and product colour during extrusion. Analysis of variance (ANOVA) showed SDS was the most important factor influencing its ability to be extruded because it detangled protein chains and allowed them to form new stabilising interactions required for consolidation. The best extruded sample, which was 98% consolidated and 49% white, contained 40 pphBM water, 10 pphBM TEG and 6 pphBM SDS

PocketPicker: analysis of ligand binding-sites with shape descriptors

Background Identification and evaluation of surface binding-pockets and occluded cavities are initial steps in protein structure-based drug design. Characterizing the active site's shape as well as the distribution of surrounding residues plays an important role for a variety of applications such as automated ligand docking or in situ modeling. Comparing the shape similarity of binding site geometries of related proteins provides further insights into the mechanisms of ligand binding. Results We present PocketPicker, an automated grid-based technique for the prediction of protein binding pockets that specifies the shape of a potential binding-site with regard to its buriedness. The method was applied to a representative set of protein-ligand complexes and their corresponding apo-protein structures to evaluate the quality of binding-site predictions. The performance of the pocket detection routine was compared to results achieved with the existing methods CAST, LIGSITE, LIGSITEcs, PASS and SURFNET. Success rates PocketPicker were comparable to those of LIGSITEcs and outperformed the other tools. We introduce a descriptor that translates the arrangement of grid points delineating a detected binding-site into a correlation vector. We show that this shape descriptor is suited for comparative analyses of similar binding-site geometry by examining induced-fit phenomena in aldose reductase. This new method uses information derived from calculations of the buriedness of potential binding-sites. Conclusions The pocket prediction routine of PocketPicker is a useful tool for identification of potential protein binding-pockets. It produces a convenient representation of binding-site shapes including an intuitive description of their accessibility. The shape-descriptor for automated classification of binding-site geometries can be used as an additional tool complementing elaborate manual inspections