Binary image representation of a ligand binding site: its application to efficient sampling of a conformational ensemble

Background  

Modelling the ligand binding site of a protein is an important component of understanding protein-ligand interactions and is being actively studied. Even if the side chains are restricted to rotamers, a set of commonly-observed low-energy conformations, the exhaustive combinatorial search of ligand binding site conformers is known as NP-hard. Here we propose a new method, ROTAIMAGE, for modelling the plausible conformers for the ligand binding site given a fixed backbone structure.     

Beyond rotamers: a generative,probabilistic model of side chains in proteins

Background  

Accurately covering the conformational space of amino acid side chains is essential for important applications such as protein design, docking and high resolution structure prediction. Today, the most common way to capture this conformational space is through rotamer libraries - discrete collections of side chain conformations derived from experimentally determined protein structures. The discretization can be exploited to efficiently search the conformational space. However, discretizing this naturally continuous space comes at the cost of losing detailed information that is crucial for certain applications. For example, rigorously combining rotamers with physical force fields is associated with numerous problems.     

Evidence for the adaptation of protein pH-dependence to subcellular pH

Background  

The availability of genome sequences, and inferred protein coding genes, has led to several proteome-wide studies of isoelectric points. Generally, isoelectric points are distributed following variations on a biomodal theme that originates from the predominant acid and base amino acid sidechain pKas. The relative populations of the peaks in such distributions may correlate with environment, either for a whole organism or for subcellular compartments. There is also a tendency for isoelectric points averaged over a subcellular location to not coincide with the local pH, which could be related to solubility. We now calculate the correlation of other pH-dependent properties, calculated from 3D structure, with subcellular pH.     

PM3 and AM1 Study on β-N-acetyl-muramic Acid and 3 Murein Related Derivatives

The energetically favoured conformations of -N-acetyl-Muramic acid, its C6-O-acetylated form, the methylamide and the methyl-glycoside have been investigated using the semiempirical PM3 and AM1 methods. All these compounds are either components or fragmentary structures of the murein network. The atomic coordinates of the starting set of the -N-acetyl-Muramic acid molecule have been obtained by a PM3 minimization of one saccharide molecule cut out from the murein single strand model proposed by Barnickel at al. [1]. The sidegroups of the derivatives have been introduced by a molecular editor. These conformations served as starting points in conformational space for a grid search by scanning all sidechain torsional angles for non-hydrogen atoms with exception of the N-acetyl group which was held in cisoid position (i.e. N2-H bond is parallel to C1-H and C3-H bond) and only minimized. The PM3 method with an additional amide correction potential and the AM1 method were used. The torsional angle distributions of the lactyl sidechain (free acid and methylamide), the C6-O-acetylated sidechain and the C1-methoxy sidechain have been investigated, showing distinct energetically favoured torsional angle regions. The results are compared to earlier studies on -N-acetyl-Muramic acid by J.S. Yadav et al. [2,3] who were using the MNDO and PCILO methods and by P.N.S. Yadav et al. [4] who were using the empirical MM2 force-field.Supplementary material to this paper is available in electronic form at http://dx.doi.org/10.1007/s0089460020190     

A new protein binding pocket similarity measure based on comparison of clouds of atoms in 3D: application to ligand prediction

Background  

Predicting which molecules can bind to a given binding site of a protein with known 3D structure is important to decipher the protein function, and useful in drug design. A classical assumption in structural biology is that proteins with similar 3D structures have related molecular functions, and therefore may bind similar ligands. However, proteins that do not display any overall sequence or structure similarity may also bind similar ligands if they contain similar binding sites. Quantitatively assessing the similarity between binding sites may therefore be useful to propose new ligands for a given pocket, based on those known for similar pockets.     

Protein sequence optimization with a pairwise decomposable penalty for buried unsatisfied hydrogen bonds

In aqueous solution, polar groups make hydrogen bonds with water, and hence burial of such groups in the interior of a protein is unfavorable unless the loss of hydrogen bonds with water is compensated by formation of new ones with other protein groups. For this reason, buried “unsatisfied” polar groups making no hydrogen bonds are very rare in proteins. Efficiently representing the energetic cost of unsatisfied hydrogen bonds with a pairwise-decomposable energy term during protein design is challenging since whether or not a group is satisfied depends on all of its neighbors. Here we describe a method for assigning a pairwise-decomposable energy to sidechain rotamers such that following combinatorial sidechain packing, buried unsaturated polar atoms are penalized. The penalty can be any quadratic function of the number of unsatisfied polar groups, and can be computed very rapidly. We show that inclusion of this term in Rosetta sidechain packing calculations substantially reduces the number of buried unsatisfied polar groups.     

Relationship between chemical shift value and accessible surface area for all amino acid atoms

Background  

Chemical shifts obtained from NMR experiments are an important tool in determining secondary, even tertiary, protein structure. The main repository for chemical shift data is the BioMagResBank, which provides NMR-STAR files with this type of information. However, it is not trivial to link this information to available coordinate data from the PDB for non-backbone atoms due to atom and chain naming differences, as well as sequence numbering changes.     

Protein evolution of ANTP and PRD homeobox genes

Background  

Although homeobox genes have been the subject of many studies, little is known about the main amino acid changes that occurred early in the evolution of genes belonging to different classes.     

ACID: annotation of cassette and integron data

Background  

Although integrons and their associated gene cassettes are present in ~10% of bacteria and can represent up to 3% of the genome in which they are found, very few have been properly identified and annotated in public databases. These genetic elements have been overlooked in comparison to other vectors that facilitate lateral gene transfer between microorganisms.     

Exploring historical trends using taxonomic name metadata

Background  

Authority and year information have been attached to taxonomic names since Linnaean times. The systematic structure of taxonomic nomenclature facilitates the ability to develop tools that can be used to explore historical trends that may be associated with taxonomy.     

A theoretical approach to predicting the success of genetic manipulation of malaria mosquitoes in malaria control

Background  

Mosquitoes that have been genetically modified to better encapsulate the malaria parasite Plasmodium falciparum are being considered as a possible tool in the control of malaria. Hopes for this have been raised with the identification of genes involved in the encapsulation response and with advances in the tools required to transform mosquitoes. However, we have only very little understanding of the conditions that would allow such genes to spread in natural populations.     

Molecular cloning and tissue expression of the fatty acid-binding protein (<Emphasis Type="Italic">Es-FABP</Emphasis>) gene in female Chinese mitten crab (<Emphasis Type="Italic">Eriocheir sinensis</Emphasis>)

Background  

Fatty acid-binding proteins (FABPs), small cytosolic proteins that function in the uptake and utilization of fatty acids, have been extensively studied in higher vertebrates while invertebrates have received little attention despite similar nutritional requirements during periods of reproductive activity.     

Autofix for backward-fit sidechains: using MolProbity and real-space refinement to put misfits in their place

Misfit sidechains in protein crystal structures are a stumbling block in using those structures to direct further scientific inference. Problems due to surface disorder and poor electron density are very difficult to address, but a large class of systematic errors are quite common even in well-ordered regions, resulting in sidechains fit backwards into local density in predictable ways. The MolProbity web site is effective at diagnosing such errors, and can perform reliable automated correction of a few special cases such as 180° flips of Asn or Gln sidechain amides, using all-atom contacts and H-bond networks. However, most at-risk residues involve tetrahedral geometry, and their valid correction requires rigorous evaluation of sidechain movement and sometimes backbone shift. The current work extends the benefits of robust automated correction to more sidechain types. The Autofix method identifies candidate systematic, flipped-over errors in Leu, Thr, Val, and Arg using MolProbity quality statistics, proposes a corrected position using real-space refinement with rotamer selection in Coot, and accepts or rejects the correction based on improvement in MolProbity criteria and on χ angle change. Criteria are chosen conservatively, after examining many individual results, to ensure valid correction. To test this method, Autofix was run and analyzed for 945 representative PDB files and on the 50S ribosomal subunit of file 1YHQ. Over 40% of Leu, Val, and Thr outliers and 15% of Arg outliers were successfully corrected, resulting in a total of 3,679 corrected sidechains, or 4 per structure on average. Summary Sentences: A common class of misfit sidechains in protein crystal structures is due to systematic errors that place the sidechain backwards into the local electron density. A fully automated method called “Autofix” identifies such errors for Leu, Val, Thr, and Arg and corrects over one third of them, using MolProbity validation criteria and Coot real-space refinement of rotamers. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

GeneBins: a database for classifying gene expression data,with application to plant genome arrays

Background  

To interpret microarray experiments, several ontological analysis tools have been developed. However, current tools are limited to specific organisms.     

Functional phosphoproteomic profiling of phosphorylation sites in membrane fractions of salt-stressed Arabidopsis thaliana

Background  

Under conditions of salt stress, plants respond by initiating phosphorylation cascades. Many key phosphorylation events occur at the membrane. However, to date only limited sites have been identified that are phosphorylated in response to salt stress in plants.     

Isolation of Cronobacter spp. (formerly Enterobacter sakazakii) from infant food, herbs and environmental samples and the subsequent identification and confirmation of the isolates using biochemical, chromogenic assays, PCR and 16S rRNA sequencing

Background  

Cronobacter spp. (formerly Enterobacter sakazakii), are a group of Gram-negative pathogens that have been implicated as causative agents of meningitis and necrotizing enterocolitis in infants. The pathogens are linked to infant formula; however, they have also been isolated from a wide range of foods and environmental samples.     

The Symbiosis Interactome: a computational approach reveals novel components,functional interactions and modules in Sinorhizobium meliloti

Background  

Rhizobium-Legume symbiosis is an attractive biological process that has been studied for decades because of its importance in agriculture. However, this system has undergone extensive study and although many of the major factors underpinning the process have been discovered using traditional methods, much remains to be discovered.     

High-throughput identification of interacting protein-protein binding sites

Background  

With the advent of increasing sequence and structural data, a number of methods have been proposed to locate putative protein binding sites from protein surfaces. Therefore, methods that are able to identify whether these binding sites interact are needed.