Contact Propensities Research Articles

Virtual Screening and Validation of Affinity DNA Functional Ligands for IgG Fc Segment.

The effective attachment of antibodies to the immune sensing interface is a crucial factor that determines the detection performance of immunosensors. Therefore, this study aims to investigate a novel antibody immobilization material with low molecular weight, high stability, and excellent directional immobilization effect. In this study, we employed molecular docking technology based on the ZDOCK algorithm to virtually screen DNA functional ligands (DNAFL) for the Fc segment of antibodies. Through a comprehensive analysis of the key binding sites and contact propensities at the interface between DNAFL and IgG antibody, we have gained valuable insights into the affinity relationship, as well as the principles governing amino acid and nucleotide interactions at this interface. Furthermore, molecular affinity experiments and competitive binding experiments were conducted to validate both the binding ability of DNAFL to IgG antibody and its actual binding site. Through affinity experiments using multi-base sequences, we identified bases that significantly influence antibody-DNAFL binding and successfully obtained DNAFL with an enhanced affinity towards the IgG Fc segment. These findings provide a theoretical foundation for the targeted design of higher-affinity DNAFLs while also presenting a new technical approach for immunosensor preparation with potential applications in biodetection.

The propensity of non-concussive and concussive head contacts during elite-level women's rugby league matches: A prospective analysis of over 14,000 tackle events.

Identify the frequency, propensity, and factors related to tackle events which result in contact with the head in elite-level women's rugby league. Prospective video analysis study. Video footage from 59 Women's Super League matches were analysed (n = 14,378 tackle events). All tackle events were coded as no head contact or head contact. Other independent variables included: area contacting head, impacted player, concussion outcome, penalty outcome, round of competition, time in match and team standard. There were 83.0 ± 20.0 (propensity 304.0/1000 tackle events) head contacts per match. The propensity of head contact was significantly greater for the tackler than ball-carrier (178.5 vs. 125.7/1000 tackle events; incident rate ratio 1.42, 95 % confidence interval 1.34 to 1.50). Head contacts occurring from an arm, shoulder, and head occurred significantly more than any other contact type. The propensity of concussions was 2.7/1000 head contacts. There was no significant influence of team standard or time in match on the propensity of head contacts. The observed head contacts can inform interventions, primarily focusing on the tackler not contacting the ball-carrier's head. The tackler's head should also be appropriately positioned to avoid contact with the ball-carrier's knee (highest propensity for concussion). The findings are consistent with other research in men's rugby. Law modifications and/or enforcement (reducing the number of un-penalised head contacts), concurrent with coaching interventions (optimising head placement or reducing the head being contacted) may help minimise head contact risk factors for women's rugby league.

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are highly dynamic systems that play an important role in cell signaling processes and their misfunction often causes human disease. Proper understanding of IDP function not only requires the realistic characterization of their three-dimensional conformational ensembles at atomic-level resolution but also of the time scales of interconversion between their conformational substates. Large sets of experimental data are often used in combination with molecular modeling to restrain or bias models to improve agreement with experiment. It is shown here for the N-terminal transactivation domain of p53 (p53TAD) and Pup, which are two IDPs that fold upon binding to their targets, how the latest advancements in molecular dynamics (MD) simulations methodology produces native conformational ensembles by combining replica exchange with series of microsecond MD simulations. They closely reproduce experimental data at the global conformational ensemble level, in terms of the distribution properties of the radius of gyration tensor, and at the local level, in terms of NMR properties including 15N spin relaxation, without the need for reweighting. Further inspection revealed that 10–20% of the individual MD trajectories display the formation of secondary structures not observed in the experimental NMR data. The IDP ensembles were analyzed by graph theory to identify dominant inter-residue contact clusters and characteristic amino-acid contact propensities. These findings indicate that modern MD force fields with residue-specific backbone potentials can produce highly realistic IDP ensembles sampling a hierarchy of nano- and picosecond time scales providing new insights into their biological function.

A unified statistical potential reveals that amino acid stickiness governs nonspecific recruitment of client proteins into condensates.

Membraneless organelles are cellular compartments that form by liquid–liquid phase separation of one or more components. Other molecules, such as proteins and nucleic acids, will distribute between the cytoplasm and the liquid compartment in accordance with the thermodynamic drive to lower the free energy of the system. The resulting distribution colocalizes molecular species to carry out a diversity of functions. Two factors could drive this partitioning: the difference in solvation between the dilute versus dense phase and intermolecular interactions between the client and scaffold proteins. Here, we develop a set of knowledge‐based potentials that allow for the direct comparison between stickiness, which is dominated by desolvation energy, and pairwise residue contact propensity terms. We use these scales to examine experimental data from two systems: protein cargo dissolving within phase‐separated droplets made from FG repeat proteins of the nuclear pore complex and client proteins dissolving within phase‐separated FUS droplets. These analyses reveal a close agreement between the stickiness of the client proteins and the experimentally determined values of the partition coefficients (R > 0.9), while pairwise residue contact propensities between client and scaffold show weaker correlations. Hence, the stickiness of client proteins is sufficient to explain their differential partitioning within these two phase‐separated systems without taking into account the composition of the condensate. This result implies that selective trafficking of client proteins to distinct membraneless organelles requires recognition elements beyond the client sequence composition.StatementEmpirical potentials for amino acid stickiness and pairwise residue contact propensities are derived. These scales are unique in that they enable direct comparison of desolvation versus contact terms. We find that partitioning of a client protein to a condensate is best explained by amino acid stickiness.

ProteinPrompt: a webserver for predicting protein-protein interactions.

Protein-protein interactions (PPIs) play an essential role in a great variety of cellular processes and are therefore of significant interest for the design of new therapeutic compounds as well as the identification of side effects due to unexpected binding. Here, we present ProteinPrompt, a webserver that uses machine learning algorithms to calculate specific, currently unknown PPIs. Our tool is designed to quickly and reliably predict contact propensities based on an input sequence in order to scan large sequence libraries for potential binding partners, with the goal to accelerate and assure the quality of the laborious process of drug target identification. We collected and thoroughly filtered a comprehensive database of known binders from several sources, which is available as download. ProteinPrompt provides two complementary search methods of similar accuracy for comparison and consensus building. The default method is a random forest (RF) algorithm that uses the auto-correlations of seven amino acid scales. Alternatively, a graph neural network (GNN) implementation can be selected. Additionally, a consensus prediction is available. For each query sequence, potential binding partners are identified from a protein sequence database. The proteom of several organisms are available and can be searched for binders. To evaluate the predictive power of the algorithms, we prepared a test dataset that was rigorously filtered for redundancy. No sequence pairs similar to the ones used for training were included in this dataset. With this challenging dataset, the RF method achieved an accuracy rate of 0.88 and an area under the curve of 0.95. The GNN achieved an accuracy rate of 0.86 using the same dataset. Since the underlying learning approaches are unrelated, comparing the results of RF and GNNs reduces the likelihood of errors. The consensus reached an accuracy of 0.89. ProteinPrompt is available online at: http://proteinformatics.org/ProteinPrompt, where training and test data used to optimize the methods are also available. The server makes it possible to scan the human proteome for potential binding partners of an input sequence within minutes. For local offline usage, we furthermore created a ProteinPrompt Docker image which allows for batch submission: https://gitlab.hzdr.de/proteinprompt/ProteinPrompt. In conclusion, we offer a fast, accurate, easy-to-use online service for predicting binding partners from an input sequence.

Alterations in 3D chromatin organization contribute to tumorigenesis of EGFR-amplified glioblastoma

BackgroundEGFR amplification and/or mutation are found in more than half of the cases with glioblastoma. Yet, the role of chromatin interactions and its regulation of gene expression in EGFR-amplified glioblastoma remains unclear. MethodsIn this study, we explored alterations in 3D chromatin organization of EGFR-amplified glioblastoma and its subsequent impact by performing a comparative analysis of Hi-C, RNA-seq, and whole-genome sequencing (WGS) on EGFR-amplified glioblastoma-derived A172 and normal astrocytes (HA1800 cell line). ResultsA172 cells showed an elevated chromatin relaxation, and unexpected entanglement of chromosome regions. A genome-wide landscape of switched compartments and differentially expressed genes between HA1800 and A172 cell lines demonstrated that compartment activation reshaped chromatin accessibility and activated tumorigenesis-related genes. Topological associating domain (TAD) analysis revealed that altered TAD domains in A172 also contribute to oncogene activation and tumor repressor deactivation. Interestingly, glioblastoma-derived A172 cells showed a different chromatin loop contact propensity. Genes in tumorigenesis-associated signaling pathways were significantly enriched at the anchor loci of altered chromatin loops. Oncogene activation and tumor repressor deactivation were associated with chromatin loop alteration. Structure variations (SVs) had a dramatic impact on the chromatin conformation of EGFR-amplified glioblastoma-derived tumor cells. Moreover, our results revealed that 7p11.2 duplication activated EGFR expression in EGFR-amplified glioblastoma via neo-TAD formation and novel enhancer-promoter interaction emergence between LINC01446 and EGFR. ConclusionsThe disordered 3D genomic map and multi-omics data of EGFR-amplified glioblastoma provide a resource for future interrogation of the relationship between chromatin interactions and transcriptome in tumorigenesis.

Study of supramolecular self-assembly of pyridone and dihydropyridone co-crystal: Synthesis, crystal structure, Hirshfeld surface, DFT and molecular docking studies

Dihydropyridone is synthesized by the multicomponent condensation reactions (MCRs), followed by three different oxidation methods to synthesize pyridone. The 3-D self-assemblies of both the compounds were determined using the single-crystal X-ray diffraction method. Dihydropyridone products are found as a racemic mixture in synthesis and crystalized as co-crystal. Similar structural conformations are observed in both the compounds but stabilized with different non-covalent interactions. Hirshfeld surface analysis is done to analyze the various intermolecular interactions in both the structure. This study gives the clue of driving force in the self-assembly of molecules in crystal lattices. The propensity of inter-molecular contacts to construct the supramolecular assembly was further studied using DFT. The geometrical optimizations of both the compounds were done by the electronic structure method using density functional theory (DFT) to identify the active sites and explore the molecules' chemically reactive parameters. Further, both compounds were docked with Survivin Protein and Kinesin Eg5 protein to analyze the binding affinity with targeted protein.

Analysis of supramolecular self-assembly of two chromene derivatives: Synthesis, crystal structure, Hirshfeld surface, quantum computational and molecular docking studies

Two 4H-chromene derivatives (1C and 1F) were synthesized by the multicomponent condensation reactions (MCRs) and spectroscopically characterized. The 3-D structures of both the compounds were determined using single crystal X-ray diffraction method. The similar structural conformations are observed in both the compounds but they are stabilized with different packing modes. The supramolecular synthons constructed by strong hydrogen bond interactions plays a major role in the supramolecular self-assembly of molecules in the solid state. Hirshfeld surface analysis is used to assess the various intermolecular interactions in both the structure that driven the self-assembly of molecules in crystal lattices. The propensity of inter-molecular contacts to construct the supramolecular assembly were analyzed using enrichment ratios. The geometrical optimization of both the structures were done by electronic structure method using density functional theory (DFT) to identify the active sites and to explore the chemically reactive parameters of the molecules. Further, novel 1C and 1F compounds were docked with DNA gyrase protein of S. aureus to analyze the binding affinity with targeted protein.

Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression.

A Bayesian Analysis of Design Parameters in Survey Data Collection

In the design of surveys, a number of input parameters such as contact propensities, participation propensities, and costs per sample unit play a decisive role. In ongoing surveys, these survey design parameters are usually estimated from previous experience and updated gradually with new experience. In new surveys, these parameters are estimated from expert opinion and experience with similar surveys. Although survey institutes have fair expertise and experience, the postulation, estimation, and updating of survey design parameters is rarely done in a systematic way. This article presents a Bayesian framework to include and update prior knowledge and expert opinion about the parameters. This framework is set in the context of adaptive survey designs in which different population units may receive different treatment given quality and cost objectives. For this type of survey, the accuracy of design parameters becomes even more crucial to effective design decisions. The framework allows for a Bayesian analysis of the performance of a survey during data collection and in between waves of a survey. We demonstrate the utility of the Bayesian analysis using a simulation study based on the Dutch Health Survey.

Analysis of nanobody paratopes reveals greater diversity than classical antibodies.

Nanobodies (Nbs) are a class of antigen-binding protein derived from camelid immune systems, which achieve equivalent binding affinities and specificities to classical antibodies (Abs) despite being comprised of only a single variable domain. Here, we use a data set of 156 unique Nb:antigen complex structures to characterize Nb–antigen binding and draw comparison to a set of 156 unique Ab:antigen structures. We analyse residue composition and interactions at the antigen interface, together with structural features of the paratopes of both data sets. Our analysis finds that the set of Nb structures displays much greater paratope diversity, in terms of the structural segments involved in the paratope, the residues used at these positions to contact the antigen and furthermore the type of contacts made with the antigen. Our findings suggest a different relationship between contact propensity and sequence variability from that observed for Ab VH domains. The distinction between sequence positions that control interaction specificity and those that form the domain scaffold is much less clear-cut for Nbs, and furthermore H3 loop positions play a much more dominant role in determining interaction specificity.

Analysis of social networks, social interactions, and out-of-home leisure activity generation: Evidence from Japan

This article analyses the connection between social networks, social interactions and out-of-home leisure activity generation in the context of Japanese society. A multilevel structural equation modelling approach is used to account for the hierarchical structure of the data. At the ego-alter (self-other) level, results suggest the existence of a complementary effect between face to face interaction and ICT contact propensity that becomes a substitution effect given increasing distance between egos and alters. Furthermore, a mediating effect by face to face interaction between ICT contact propensity and distance was observed. At the ego (self) level, urbanization level, income, network size and club membership were found to have a direct positive effect on leisure propensity and indirectly on ICT contact propensity, while an extraverted personality was positively associated with higher ICT contact propensity.

Atom interaction propensities of oxygenated chemical functions in crystal packings.

The crystal contacts of several families of hydrocarbon compounds substituted with one or several types of oxygenated chemical groups were analyzed statistically using the Hirshfeld surface methodology. The propensity of contacts to occur between two chemical types is described with the contact enrichment descriptor. The systematic large enrichment ratios of some interactions like the O-H⋯O hydrogen bonds suggests that these contacts are a driving force in the crystal packing formation. The same statement holds for the weaker C-H⋯O hydrogen bonds in ethers, esters and ketones, in the absence of polar H atoms. The over-represented contacts in crystals of oxygenated hydrocarbons are generally of two types: electrostatic attractions (hydrogen bonds) and hydrophobic interactions. While Cl⋯O interactions are generally avoided, in a minority of chloro-oxygenated hydrocarbons, significant halogen bonding does occur. General tendencies can often be derived for many contact types, but outlier compounds are instructive as they display peculiar or rare features. The methodology also allows the detection of outliers which can be structures with errors. For instance, a significant number of hydroxylated molecules displaying over-represented non-favorable oxygen-oxygen contacts turned out to have wrongly oriented hydroxyl groups. Beyond crystal packings with a single molecule in the asymmetric unit, the behavior of water in monohydrate compounds and of crystals with Z' = 2 (dimers) are also investigated. It was found in several cases that, in the presence of several oxygenated chemical groups, cross-interactions between different chemical groups (e.g. water/alcohols; alcohols/phenols) are often favored in the crystal packings. While some trends in accordance with common chemical principles are retrieved, some unexpected results can however appear. For example, in crystals of alcohol-phenol compounds, the strong O-H⋯O hydrogen bonds between two phenol groups turn out to be extremely rare, while cross contacts between phenols and alcohols have enriched occurrences.

Structural, crystal structure, Hirshfeld surface analysis and physicochemical studies of a new chlorocadmate template by 1-(2-hydroxyethyl)piperazine

The synthesis, crystal structure and spectroscopic characterization of a new chlorocadmate template by the 1-(2-hydroxyethyl)piperazine ligand are reported. In the atomic arrangement, the CdCl5O entities are deployed in corrugated rows along the a-axis at y = 1/4 and y = 3/4 to form layers parallel to the (a,b) plane. In these crystals, piperazinediium cations are in a chair conformation and are inserted between these layers through NH⋯Cl, CH⋯Cl, OH⋯Cl and NH⋯O hydrogen bonds to form infinite three-dimensional network.Investigation of intermolecular interactions and crystal packing via Hirshfeld surface analysis reveals that H⋯Cl and CH⋯HC intermolecular interactions are the most abundant contacts of the organic cation in the crystal packing. The crystal contacts enrichments reveals that, the Cd++ … Cl− salt bridges, the Cd⋯O complexation and OH⋯Cl- and NH⋯Cl-strong H-bonds are the driving forces in the packing formation. The presence of twelve independent chloride anions and four organic cation in the asymmetric unit allowed comparing their contact propensities. The 13C and 15N CP-MAS NMR spectra are in agreement with the X-ray structure. Additional characterization of this compound has also been performed by IR spectroscopy.

Conformational Equilibrium between the Sub States of the Acidic Denatured State of ACBP Determined by NMR Chemical Shifts and Metadynamics

NMR Chemical shifts have recently gain renovated attention as a probe for both the structure and the dynamics of proteins. The structure and the dynamics of folded proteins can be elucidated straightforwardly from the backbone chemical shifts at least for small to medium sized protein. In the denatured state and for intrinsically disordered proteins chemical shifts are routinely used as probe for secondary structure propensities and populations and have been also used as a probe for tertiary structure contact propensities. In this work we show how chemical shifts, together with an appropriate advanced sampling method, can be successfully used to determine the structure and the dynamics of the denatured state of ACBP, an 86 residues long proteins, in acidic conditions. Chemical shifts are used as replica-averaged restrained to improve the quality of the molecular mechanic force field in the Maximum Entropy framework and Bias-Exchange Metadynamics is used to achieve a converged sampling of the large conformational space of an unfolded protein.View Large Image | View Hi-Res Image | Download PowerPoint Slide

Solvated protein–protein docking using Kyte‐Doolittle‐based water preferences

HADDOCK is one of the few docking programs that can explicitly account for water molecules in the docking process. Its solvated docking protocol starts from hydrated molecules and a fraction of the resulting interfacial waters is subsequently removed in a biased Monte Carlo procedure based on water-mediated contact probabilities. The latter were derived from an analysis of water contact frequencies from high-resolution crystal structures. Here, we introduce a simple water-mediated amino acid-amino acid contact probability scale derived from the Kyte-Doolittle hydrophobicity scale and assess its performance on the largest high-resolution dataset developed to date for solvated docking. Both scales yield high-quality docking results. The novel and simple hydrophobicity scale, which should reflect better the physicochemical principles underlying contact propensities, leads to a performance improvement of around 10% in ranking, cluster quality and water recovery at the interface compared with the statistics-based original solvated docking protocol.

Tailored Fieldwork Design to Increase Representative Household Survey Response: An Experiment in the Survey of Consumer Satisfaction

SummaryWe used a tailored survey design to obtain a more representative response. Paradata from previous consumer sentiments surveys and register information were used to stratify the sample into groups that differed in contact and co-operation propensity. We approached an experimental sample of 3000 households with a Web–mail–computer-assisted telephone interviewing sequential mixed mode strategy. The choice of initial mode and the subsequent computer-assisted telephone interviewing approach were tailored to the expected contact and co-operation propensities of the sample units. In the computer-assisted telephone interviewing follow-up of non-respondents, co-operation was manipulated by assigning specific interviewers to specific sample units. Contact was manipulated by timing, spacing and prioritizing calls. The tailored fieldwork strategy was successful in significantly increasing representativeness, while maintaining the level of response and costs. Representativeness was determined by R-indicators.

Fabrication of superhydrophobic films with robust adhesion and dual pinning state via in situ polymerization

Superhydrophobic films on glass substrate with robust adhesion and dual pinning to the water droplets were fabricated utilizing a novel in situ polymerized fluorinated polybenzoxazine (F-PBZ) having drooping aliphatic chains and incorporated SiO2 nanoparticles (SiO2 NPs). By employing the F-PBZ/SiO2 NPs modification, the as-prepared composite films possess the robust adhesion to the glass substrate and superhydrophobic pinned state with water contact angle (WCA) of 150° and the non-pinned state with WCA approaching to 165°. Surface morphological studies have indicated that the wettability of the resultant films could be controlled by tuning the surface composition as well as the hierarchical structures. The key role of micro and sub-micro-sized structures and the nanometer sized voids is discussed by the investigation into static contact angle, contact angle hysteresis, droplet evaporation, and propensity for air pocket formation. The as-prepared films exhibited high adhesion toward the glass substrate with considerable durability in corrosive water and proved their simultaneous use in the transportation of micro-droplets, which could be helpful to design large-area and highly scalable superhydrophobic films.

Evaluation performance of substitution matrices, based on contacts between residue terminal groups

Sequence alignment is a standard method for the estimation of the evolutionary, structural, and functional relationships among amino acid sequences. The quality of alignments depends on the used similarity matrix. Statistical contact potentials (CPs) contain information on contact propensities among residues in native protein structures. Substitution matrices (SMs) based on CPs are applicable for the comparison of distantly related sequences. Here, contact between amino acids was estimated on the basis of the evaluation of the distances between side-chain terminal groups (SCTGs), which are defined as the group of the side-chain heavy atoms with fixed distances between them. In this paper, two new types of CPs and similarity matrices have been constructed: one based on fixed cutoff distance obtained from geometric characteristics of the SCTGs (TGC1), while the other is distance-dependent potential (TGC2). These matrices are compared with other popular SMs. The performance of the matrices was evaluated by comparing sequence with structural alignments. The obtained results show that TGC2 has the best performance among contact-based matrices, but on the whole, contact-based matrices have slightly lower performance than other SMs except fold-level similarity.

Detection and Transmission of Dientamoeba fragilis from Environmental and Household Samples

Dientamoeba fragilis is a commonly occurring pathogenic protozoan often detected at higher rates in stool samples than Giardia intestinalis. However, little is known about its life cycle and mode of transmission. A total of 210 environmental and household samples were examined for the presence of D. fragilis by culture and polymerase chain reaction. Of 100 environmental samples, D. fragilis was detected only in untreated sewage. In the household samples D. fragilis was detected in 30% of household contacts tested and was not detected in any domestic pets. This study provides evidence that environmental transmission of D. fragilis is unlikely and that pets played no role in transmission of the disease in this study. Direct transmission from infected persons is the most likely mode of transmission for D. fragilis. The study also highlights the need for household contacts to be screened, given the propensity of close contacts to become infected with the organism.