Structural Dynamics of Neutral Amino Acid Transporter SLC6A19 in Simple and Complex Lipid Bilayers.

B0AT1 (SLC6A19) is a major sodium-coupled neutral amino acid transporter that relies on angiotensin converting enzyme 2 (ACE2) or collectrin for membrane trafficking. Despite its significant role in disorders associated with amino acid metabolism, there is a deficit of comprehensive structure-function understanding of B0AT1 in lipid environment. Herein, we have employed molecular dynamics (MD) simulations to explore the architectural characteristics of B0AT1 in two distinct environments: a simplified POPC bilayer and a complex lipid system replicating the native membrane composition.

TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver.

Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice.

Visualizing liquid-liquid phase transitions.

Liquid-liquid phase condensation governs a wide range of protein-protein and protein-RNA interactions in vivo and drives the formation of membrane-less compartments such as the nucleolus and stress granules. We have a broad overview of the importance of multivalency and protein disorder in driving liquid-liquid phase transitions. However, the large and complex nature of key proteins and RNA components involved in forming condensates such as stress granules has inhibited a detailed understanding of how condensates form and the structural interactions that take place within them.

Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils.

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils.

Investigating the Role of OsHDT701 and Other Blast-Associated Negative Regulatory Genes in Indica Rice Cultivar Ranjit Using Combined Wet Lab and Computational Approaches.

Rice blast, caused by Magnaporthe oryzae, severely impacts global rice production. Understanding the role of the host's blast negative regulatory genes is crucial for combating this disease. We studied the expression of seven rice blast negative regulatory genes (previously characterized in ssp.

Formulation of next-generation polyvalent vaccine candidates against three important poxviruses by targeting DNA-dependent RNA polymerase using an integrated immunoinformatics and molecular modeling approach.

Background: Poxviruses comprise a group of large double-stranded DNA viruses and are known to cause diseases in humans, livestock animals, and other animal species. The Mpox virus (MPXV; formerly Monkeypox), variola virus (VARV), and volepox virus (VPXV) are among the prevalent poxviruses of the Orthopoxviridae genera. The ongoing Mpox infectious disease pandemic caused by the Mpox virus has had a major impact on public health across the globe.

Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in α-Synuclein Fibrils.

Aberrant aggregation of α-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies. Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived α-Synuclein fibrils, which contain a non-proteinaceous, "mystery density" at the core of the protofilaments, hypothesized to be highly negatively charged. Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates α-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in α-Synuclein fibrils.

Classical molecular dynamics simulation identifies catechingallate as a promising antiviral polyphenol against MPOX palmitoylated surface protein.

Cumulative global prevalence of the emergent monkeypox (MPX) infection in the non-endemic countries has been professed as a global public health predicament. Lack of effective MPX-specific treatments sets the baseline for designing the current study. This research work uncovers the effective use of known antiviral polyphenols against MPX viral infection, and recognises their mode of interaction with the target F13 protein, that plays crucial role in formation of enveloped virions.

NMR insights into β-Lactamase activity of UVI31+ Protein from Chlamydomonas reinhardtii.

β-Lactamases (EC 3.5.2.

Spectroscopic insights with molecular docking and molecular dynamic simulation studies of anticancer drug 5-Fluorouracil targeting human pyruvate kinase m2.

This study was conducted to test the efficacy of 5-fluorouracil (5-FU) as an anticancer drug against the human pyruvate kinase isozyme M2 (PKM2) using spectroscopic, molecular docking and molecular dynamic simulation studies. PKM2 fluorescence quenching studies in the presence of 5-FU performed at three different temperatures indicates dynamic quenching processes with single-set of binding ( ≈ 1) profile. The biomolecular quenching constants () and the effective binding constants () obtained are shown to increase with temperature.

Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of a potential target for antimycotics.

Resistance to azoles and amphotericin B especially in is a growing concern towards the treatment of invasive fungal infection. At this critical juncture, intein splicing would be a productive, and innovative target to establish therapies against resistant strains. Intein splicing is the central event for the activation of host protein, essential for the growth and survival of various microorganisms including .

Inhibition potential of natural flavonoids against selected omicron (B.1.19) mutations in the spike receptor binding domain of SARS-CoV-2: a molecular modeling approach.

The omicron (B.1.19) variant of contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered a variant of concern (VOC) due to its increased transmissibility and highly infectious nature.

Illuminating the structural basis of human neurokinin 1 receptor (NK1R) antagonism through classical all-atoms molecular dynamics simulations.

Advances in structural biology have bestowed insights into the pleiotropic effects of neurokinin 1 receptors (NK1R) in diverse patho-physiological processes, thereby highlighting the potential therapeutic value of antagonists directed against NK1R. Herein, we investigate the mode of antagonist recognition to discern the obscure atomic facets germane for the function and molecular determinants of NK1R. To commence discernment of potent antagonists and the conformational changes in NK1R, induced upon antagonist binding, state-of-the-art classical all-atoms molecular dynamics (MD) simulations in lipid mimetic bilayers have been utilized.

Computational saturation mutagenesis to explore the effect of pathogenic mutations on extra-cellular domains of TREM2 associated with Alzheimer's and Nasu-Hakola disease.

Context: The specialised family of triggering receptors expressed on myeloid cells (TREMs) plays a pivotal role in causing neurodegenerative disorders and activating microglial anti-inflammatory responses. Nasu-Hakola disease (NHD), a rare autosomal recessive disorder, has been associated with mutations in TREM2, which is also responsible for raising the risk of Alzheimer's disease (AD). Herein, we have made an endeavour to differentiate the confirmed pathogenic variants in TREM2 extra-cellular domain (ECD) linked with NHD and AD using mutation-induced fold stability change (∆∆G), with the computation of 12distinct structure-based methods through saturation mutagenesis.

Dissecting the Molecular Basis of Host Leucine-Rich Repeat Containing 15 Mediated Interaction with Receptor Binding Domain of SARS-CoV-2 Spike Protein: A Computational Approach.

The detection of leucine-rich repeat containing 15 (LRRC15) as a connecting link with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the possibility of its involvement in differential restriction activity of SARS-CoV-2 pathways. However, the structure-function mechanism of LRRC15 involving the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and their mode of interaction is largely unknown. Using state-of-the-art AlphaFold2 and all-atom molecular dynamics simulations, our findings provide evidences of alternative binding modes of RBD with LRR units of LRRC15 having varied affinities.

Exploiting the potential of natural polyphenols as antivirals against monkeypox envelope protein F13 using machine learning and all-atoms MD simulations.

The re-emergence of monkeypox (MPX), in the era of COVID-19 pandemic is a new global menace. Regardless of its leniency, there are chances of MPX expediting severe health deterioration. The role of envelope protein, F13 as a critical component for production of extracellular viral particles makes it a crucial drug target.

Computational study on Schiff base derived salicylaldehyde and furfuraldehyde derivatives as potent anti-tubercular agents: prospect to dihydropteroate synthase inhibitors.

Nowadays, bacterial multidrug resistance has become a commonplace problem in clinics due to several intrinsic factors mediated through resistance to antibacterials obtained bacterial consortia and extrinsic factors, such as non-uniform antibacterial policy and migration of resistant bacteria through human and other routes. The development of newer, effective anti-mycobacterial candidate(s) is coveted by clinics. Hybrid molecules would be comparatively more emulating against invasive bacterial strains; nevertheless, newer antibiotics are continually added.

Structural insights of (catla) myxovirus resistance protein,GTP binding recognition and constitutive expression induced with Poly I:C.

The Myxovirus resistance () proteins are critical effectors belonging to the super-family of guanidine triphosphatase, often stimulated by type I interferon (IFN) and mediates antiviral responses to restrict the replication of numerous viral genes in fishes. In teleosts, Mx proteins display diverse and complicated antiviral activity in different species. The present investigation seeks to characterize the Mx gene from upon induction by double-stranded (ds) RNA, polyinosinic-polycytidylic acid, (poly I: C).

Machine learning and classical MD simulation to identify inhibitors against the P37 envelope protein of monkeypox virus.

Monkeypox virus (MPXV) outbreak is a serious public health concern that requires international attention. P37 of MPXV plays a pivotal role in DNA replication and acts as one of the promising targets for antiviral drug design. In this study, we intent to screen potential analogs of existing FDA approved drugs of MPXV against P37 using state-of-the-art machine learning and computational biophysical techniques.

All-atoms molecular dynamics study to screen potent efflux pump inhibitors against KpnE protein of .

The Small Multidrug Resistance efflux pump protein KpnE, plays a pivotal role in multi-drug resistance in . Despite well-documented study of its close homolog, EmrE, from , the mechanism of drug binding to KpnE remains obscure due to the absence of a high-resolution experimental structure. Herein, we exclusively elucidate its structure-function mechanism and report some of the potent inhibitors through drug repurposing.

Structural insights into SARS-CoV-2 main protease conformational plasticity.

The spread of different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants underscores the need for insights into the structural properties of its structural and non-structural proteins. The highly conserved homo-dimeric chymotrypsin-like protease (3CL M ), belonging to the class of cysteine hydrolases, plays an indispensable role in processing viral polyproteins that are involved in viral replication and transcription. Studies have successfully demonstrated the role of M as an attractive drug target for designing antiviral treatments because of its importance in the viral life cycle.