Multiscale simulations reveal architecture of NOTCH protein and ligand specific features.

NOTCH, a single-pass transmembrane protein, plays a crucial role in cell fate determination through cell-to-cell communication. It interacts with two canonical ligands, Delta-like (DLL) and Jagged (JAG), located on neighboring cells to regulate diverse cellular processes. Despite extensive studies on the functional roles of NOTCH and its ligands in cellular growth, the structural details of full-length NOTCH and its ligands remain poorly understood.

A new discrete-geometry approach for integrative docking of proteins using chemical crosslinks.

The structures of protein complexes allow us to understand and modulate the biological functions of the proteins. Integrative docking is a computational method to obtain the structures of a protein complex, given the atomic structures of the constituent proteins along with other experimental data on the complex, such as chemical crosslinks or SAXS profiles. Here, we develop a new discrete geometry-based method, wall-EASAL, for integrative rigid docking of protein pairs given the structures of the constituent proteins and chemical crosslinks.

The molecular architecture of the desmosomal outer dense plaque by integrative structural modeling.

Desmosomes mediate cell-cell adhesion and are prevalent in tissues under mechanical stress. However, their detailed structural characterization is not available. Here, we characterized the molecular architecture of the desmosomal outer dense plaque (ODP) using Bayesian integrative structural modeling via the Integrative Modeling Platform.

BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections.

The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC) of 0.

StrIDR: a database of intrinsically disordered regions of proteins with experimentally resolved structures.

Motivation: Intrinsically disordered regions (IDRs) of proteins exist as an ensemble of conformations, and not as a single structure. Existing databases contain extensive, experimentally derived annotations of intrinsic disorder for millions of proteins at the sequence level. However, only a tiny fraction of these IDRs are associated with an experimentally determined protein structure.

Intracellular peroxynitrite perturbs redox balance, bioenergetics, and Fe-S cluster homeostasis in Mycobacterium tuberculosis.

The ability of Mycobacterium tuberculosis (Mtb) to tolerate nitric oxide (NO) and superoxide (O) produced by phagocytes contributes to its success as a human pathogen. Recombination of NO and O generates peroxynitrite (ONOO), a potent oxidant produced inside activated macrophages causing lethality in diverse organisms. While the response of Mtb toward NO and O is well established, how Mtb responds to ONOO remains unclear.

Plasticity of the proteasome-targeting signal Fat10 enhances substrate degradation.

The proteasome controls levels of most cellular proteins, and its activity is regulated under stress, quiescence, and inflammation. However, factors determining the proteasomal degradation rate remain poorly understood. Proteasome substrates are conjugated with small proteins (tags) like ubiquitin and Fat10 to target them to the proteasome.

Insect Flight: State of the Field and Future Directions.

The evolution of flight in an early winged insect ancestral lineage is recognized as a key adaptation explaining the unparalleled success and diversification of insects. Subsequent transitions and modifications to flight machinery, including secondary reductions and losses, also play a central role in shaping the impacts of insects on broadscale geographic and ecological processes and patterns in the present and future. Given the importance of insect flight, there has been a centuries-long history of research and debate on the evolutionary origins and biological mechanisms of flight.

Imprinting reversible deformations on a compressed soft rod network.

We present emergent behaviour of storing mechanical deformation in compressed soft cellular materials (a network of soft polymeric rods). Under an applied compressive strain field, the soft cellular material transits from an elastic regime to a 'pseudo-plastic' regime (not to be confused with pseudoplasticity in fluids). In the elastic phase, it is capable of forgetting (or relaxing) any applied indentation once the applied indentation is removed.

The Thermodynamic Properties of Fat10ylated Proteins Are Regulated by the Fat10ylation Site.

Degradation of proteins by the proteasome is crucial in regulating their levels in the cell. Post-translational modifications, such as ubiquitylation and Fat10ylation, trigger proteasomal degradation of the substrate proteins. While ubiquitylation regulates multiple cellular pathways, Fat10ylation functions explicitly in the inflammatory response pathway.

Optimizing representations for integrative structural modeling using Bayesian model selection.

Motivation: Integrative structural modeling combines data from experiments, physical principles, statistics of previous structures, and prior models to obtain structures of macromolecular assemblies that are challenging to characterize experimentally. The choice of model representation is a key decision in integrative modeling, as it dictates the accuracy of scoring, efficiency of sampling, and resolution of analysis. But currently, the choice is usually made ad hoc, manually.

Optimizing representations for integrative structural modeling using Bayesian model selection.

Motivation: Integrative structural modeling combines data from experiments, physical principles, statistics of previous structures, and prior models to obtain structures of macromolecular assemblies that are challenging to characterize experimentally. The choice of model representation is a key decision in integrative modeling, as it dictates the accuracy of scoring, efficiency of sampling, and resolution of analysis. But currently, the choice is usually made , manually.

Interfacial residues in protein-protein complexes are in the eyes of the beholder.

Interactions between proteins are vital in almost all biological processes. The characterization of protein-protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for biotechnological and clinical purposes. The interface residues of a protein-protein complex are assumed to have the following two properties: (a) they always interact with a residue of a partner protein, which forms the basis for distance-based interface residue identification methods, and (b) they are solvent-exposed in the isolated form of the protein and become buried in the complex form, which forms the basis for Accessible Surface Area (ASA)-based methods.

The molecular architecture of the desmosomal outer dense plaque by integrative structural modeling.

Desmosomes mediate cell-cell adhesion and are prevalent in tissues under mechanical stress. However, their detailed structural characterization is not available. Here, we characterized the molecular architecture of the desmosomal outer dense plaque (ODP) using Bayesian integrative structural modeling the Integrative Modeling Platform.

Decoding the Assembly of Mixed and Branched Heterotypic Ubiquitin Chains.

Ubiquitination is a post-translational modification that regulates cell signaling, immune response, protein processing, molecular trafficking, and DNA repair. Generally, molecular trafficking and DNA repair processes need the attachment of a single ubiquitin on a substrate, known as monoubiquitination. The other functions of ubiquitin require the assembly of polymeric ubiquitin chains on the substrate, known as polyubiquitination.

Cellular compartmentalisation and receptor promiscuity as a strategy for accurate and robust inference of position during morphogenesis.

Precise spatial patterning of cell fate during morphogenesis requires accurate inference of cellular position. In making such inferences from morphogen profiles, cells must contend with inherent stochasticity in morphogen production, transport, sensing and signalling. Motivated by the multitude of signalling mechanisms in various developmental contexts, we show how cells may utilise multiple tiers of processing (compartmentalisation) and parallel branches (multiple receptor types), together with feedback control, to bring about fidelity in morphogenetic decoding of their positions within a developing tissue.

Benchmarking performance of an automatic polysomnography scoring system in a population with suspected sleep disorders.

Aim: The current gold standard for measuring sleep disorders is polysomnography (PSG), which is manually scored by a sleep technologist. Scoring a PSG is time-consuming and tedious, with substantial inter-rater variability. A deep-learning-based sleep analysis software module can perform autoscoring of PSG.

Regulatory mechanisms of c-di-AMP synthase from Mycobacterium smegmatis revealed by a structure: Function analysis.

Cyclic-di-nucleotide-based secondary messengers regulate various physiological functions, including stress responses in bacteria. Cyclic diadenosine monophosphate (c-di-AMP) has recently emerged as a crucial second messenger with implications in processes including osmoregulation, antibiotic resistance, biofilm formation, virulence, DNA repair, ion homeostasis, and sporulation, and has potential therapeutic applications. The contrasting activities of the enzymes diadenylate cyclase (DAC) and phosphodiesterase (PDE) determine the equilibrium levels of c-di-AMP.

Active enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundaries.

Vertebrate genomes are partitioned into chromatin domains or topologically associating domains (TADs), which are typically bound by head-to-head pairs of CTCF binding sites. Transcription at domain boundaries correlates with better insulation; however, it is not known whether the boundary transcripts themselves contribute to boundary function. Here we characterize boundary-associated RNAs genome-wide, focusing on the disease-relevant and TAD.

A dimer between monomers and hexamers-Oligomeric variations in glucosamine-6-phosphate deaminase family.

In bacteria that live in hosts whose terminal sugar is a sialic acid, Glucosamine-6-phosphate deaminase (NagB) catalyzes the last step in converting sialic acid into Fructose-6-phosphate. These bacteria then use the Fructose-6-phosphate as an energy source. The enzyme NagB exists as a hexamer in Gram-negative bacteria and is allosterically regulated.

Sample size requirement for achieving multisite harmonization using structural brain MRI features.

When data is pooled across multiple sites, the extracted features are confounded by site effects. Harmonization methods attempt to correct these site effects while preserving the biological variability within the features. However, little is known about the sample size requirement for effectively learning the harmonization parameters and their relationship with the increasing number of sites.

Building Indian Biomedical Leadership to Bridge the Gap Between Science, Primary Health Care and Public Health.

The Indian biomedical landscape has been characterized by the existence of somewhat polarized institutional structures and professional growth. While some scientific and public health challenges have been met with existing structures, there is still a large unmet scientific and public health need. Broadly, the physical separation of science, engineering, medical campuses and industry has led to silos of excellence and accomplishment with huge gaps in innovation and implementation.

Mechanistic Investigations on N-C Bond Cleavages in Dibasic Peptides Containing Internal Lys and Arg Residues.

The model nonapeptide AAARAAKAG* (* indicates amide) is used to explore N-C bond fragmentation under CID-MS conditions. Neighboring group participation and the effect of positioning of Lys and Arg residues on N-C bond cleavage is established using a library of synthetic peptide analogues. The importance of the Arg residue at position 4 and the to +3 spacing between Arg and Lys residues in determining the formation of the N-C bond cleaved product ions () is demonstrated by a comparative MS study of positional variants in analogue peptides.