The Shape of Science

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Insights into the structure and 3D spatial arrangement of the b-ketoacyl carrier protein synthases

The b-ketoacyl carrier protein synthases (the KAS enzymes) are key enzymes that can be used as potential anti-Plasmodium drug targets. In bacteria, three KAS enzymes have been identified (KAS I, KAS II and KAS III), whilst in Plasmodium a KAS I/II and KAS III enzyme has been reported. The protein has a total of four active sites, which have been found to be different to each other, rather than four copies of the same active site. The active sites differ not only in the type of interaction they establish with the ligand, but, in the case of Cerulenin as a ligand, the active sites of the KAS I/II enzyme also differ in the number of residues involved in the ligand protein interaction. This is very interesting biochemically, because these differences imply that the affinity of each active site for binding to the ligand might be different as well.  

Current viral infections and epidemics of flaviviridae; lots of grief but also some hope

Flaviviridae is a family of RNA viruses that includes numerous important human and animal pathogens. Recent studies on subgenomic flaviviridae replicons have revealed that the non-structural (NS) proteins, which are encoded by the C-terminal part of the polyprotein, play a crucial role in viral RNA replication. Accordingly, these proteins are assumed to form replication complexes in conjunction with genomic RNA and possibly with other cellular factors. One the most important non-structural enzymes that plays a key role in the life cycle of flaviviridae viruses is the viral helicase. Sequence alignments of the viral helicases from this family identified several conserved sequence motifs that are important for biological functions. Herein, an effort is made to summarize the current epidemics associated with the flaviviridae family worldwide, the potential of helicase enzymes as a promising pharmacological target and the use of nucleoside analogs as simple, efficient and rather versatile antiviral agents

Molecular modelling study of the 3D structure of the biglycan core protein, using homology modelling techniques

Herein we report the establishment of the 3D structure of the biglycan core protein, using conventional homology molecular modelling techniques. The 3D model has been structurally optimised via molecular dynamics.  It was found that the final model of biglycan resembles in structure its template protein bearing a set of distinct parallel β-sheet structure patterns. The biglycan model bears a very hydrophobic amino acid region towards its inner cavity that acquires an arc-like structure. The external domain of the biglycan model is made up of hydrophilic residues that are exposed to the water solvent. It is those hydrophilic residues that are responsible for their interaction with polysaccharide polymers. Overall comparison of the model of biglycan to the recently determined x-ray structure of the same protein returns a very low Root Mean Square Deviation (RMSD), which confirms the viability of the model and its reliability as a platform for the study biglycan interactions.

3D structural analysis of proteins using electrostatic surfaces based on image segmentation

Herein, we present a novel strategy to analyse and characterize proteins using protein molecular electrostatic surfaces. Our approach starts by calculating a series of distinct molecular surfaces for each protein that are subsequently flattened out, thus reducing 3D information noise. RGB images are appropriately scaled by means of standard image processing techniques whilst retaining the weight information of each protein’s molecular electrostatic surface. Then homogeneous areas in the protein surface are estimated based on unsupervised clustering of the 3D images, while performing similarity searches. This is a computationally fast approach, which efficiently highlights interesting structural areas among a group of proteins. Multiple protein electrostatic surfaces can be combined together and in conjunction with their processed images, they can provide the starting material for protein structural similarity and molecular docking experiments.  

A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses

CADASIL disease belongs to the group of rare diseases. It is well established that the Notch3 protein is primarily responsible for the development of CADASIL syndrome. Herein, we attempt to shed light to the actual molecular mechanism underlying CADASIL via insights that we have from preliminary in silico and proteomics studies on the Notch3 protein. At the moment, we are aware of a series of Notch3 point mutations that promote CADASIL. In this direction, we investigate the nature, extent, physicochemical and structural significance of the mutant species in an effort to identify the underlying mechanism of Notch3 role and implications in cell signal transduction. Overall, our in silico study has revealed a rather complex molecular mechanism of Notch3 on the structural level; depending of the nature and position of each mutation, a consensus significant loss of beta-sheet structure is observed throughout all in silico modeled mutant/wild type biological systems