Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The "blind" docking ...problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.This protocol narrows the docking search to the most relevant parts of the conformational space. This is achieved by pre-folding the free peptide and by computationally detecting anchoring spots on the surface of the unbound protein. Multiple flexible simulated annealing molecular dynamics (SAMD) simulations are subsequently carried out, starting from pre-folded peptide conformations, constrained to the various precomputed anchoring spots.Here, AnchorDock is demonstrated using two known protein-peptide complexes. A PDZ-peptide complex provides a relatively easy case due to the relatively small size of the protein, and a typical peptide conformation and binding region; a more challenging example is a complex between USP7
and a p53-derived peptide, where the protein is larger, and the peptide conformation and a binding site are generally assumed to be unknown. AnchorDock returned native-like solutions ranked first and third for the PDZ and USP7 complexes, respectively. We describe the procedure step by step and discuss possible modifications where applicable.
► The article presents molecular modeling of GTHs and GTHRs of tilapia, trout and eel. ► Each of the gonadotropins of eel, trout tilapia and human activated its own cognate receptors. ► Tilapia LHR ...was activated by hCG and eel LHR was activated by hFSH, hCG, and trout FSH. ► For FSHR, the only cross-reactivity detected was for hFSHR, which was activated by pFSH and bFSH.
The gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and their receptors play critical roles in vertebrate reproduction. In order to study intra- and interspecies ligand promiscuity of gonadotropins, COS-7 cells were transiently transfected with one of the gonadotropin receptor genes, FSHR or LHR, and tested for activation by gonadotropins from representative fish orders: Aquilliformes (eel; e), Salmoniformes (trout; tr), and Perciformes (tilapia; ta), and of mammalian origin: porcine (p), bovine (b) and human (h).
The study reveals complex relations between the gonadotropin hormones and their receptors. Each gonadotropin activated its own cognate receptor. However, taLHR was also activated by hCG and eLHR was activated by hFSH, hCG, and trFSH. For FSHR, the only cross-reactivity detected was for hFSHR, which was activated by pFSH and bFSH. These findings are of great interest and applicability in the context of activation of various GTHRs by their ligands and by ligands from other vertebrates. Analysis of the three-dimensional models of the structures highlights the importance of residues outside of the currently established hormone-receptor interface region. In addition, the interface residues in taFSHR and the effect of exon duplication, which causes an insert in the LRR domain, are suggested to affect the interaction and binding of taFSH.
There is a prevailing view that humans' capacity to use language to characterize sensations like odors or tastes is poor, providing an unreliable source of information.
Here, we developed a machine ...learning method based on Natural Language Processing (NLP) using Large Language Models (LLM) to predict COVID-19 diagnosis solely based on text descriptions of acute changes in chemosensation, i.e., smell, taste and chemesthesis, caused by the disease. The dataset of more than 1500 subjects was obtained from survey responses early in the COVID-19 pandemic, in Spring 2020.
When predicting COVID-19 diagnosis, our NLP model performs comparably (AUC ROC ~ 0.65) to models based on self-reported changes in function collected via quantitative rating scales. Further, our NLP model could attribute importance of words when performing the prediction; sentiment and descriptive words such as "smell", "taste", "sense", had strong contributions to the predictions. In addition, adjectives describing specific tastes or smells such as "salty", "sweet", "spicy", and "sour" also contributed considerably to predictions.
Our results show that the description of perceptual symptoms caused by a viral infection can be used to fine-tune an LLM model to correctly predict and interpret the diagnostic status of a subject. In the future, similar models may have utility for patient verbatims from online health portals or electronic health records.
Sweet taste of heavy water Ben Abu, Natalie; Mason, Philip E; Klein, Hadar ...
Communications biology,
04/2021, Letnik:
4, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively ...demonstrate that humans are, nevertheless, able to distinguish D
O from H
O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D
O over H
O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D
O but not by H
O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D
O in human sensory tests, as well as the calcium release elicited by D
O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.
Peptides are important signaling modules, acting both as individual hormones and as parts of larger molecules, mediating their protein-protein interactions. Many peptidic and peptidomimetic drugs ...have reached the marketplace and opportunities for peptide-based drug discovery are on the rise. pH-dependent behavior of peptides is well documented in the context of misfolding diseases and peptide translocation. Changes in the protonation states of peptide residues often have a crucial effect on a peptide's structure, dynamics and function, which may be exploited for biotechnological applications. The current review surveys the increasing levels of sophistication in the treatment of protonation states in computational studies involving peptides. Specifically we describe I) the common practice of assigning a single protonation state and using it throughout the dynamic simulation, II) approaches that consider multiple protonation states and compare computed observables to experimental ones, III) constant pH molecular dynamics methods that couple changes in protonation states with conformational dynamics "on the fly". Applications of conformational dynamics treatment of peptides in the context of binding, folding and interactions with the membrane are presented, illustrating the growing body of work in this field and highlighting the importance of careful handling of protonation states of peptidic residues.
Abstract
Background
Clinical diagnosis of coronavirus disease 2019 (COVID-19) is essential to the detection and prevention of COVID-19. Sudden onset of loss of taste and smell is a hallmark of ...COVID-19, and optimal ways for including these symptoms in the screening of patients and distinguishing COVID-19 from other acute viral diseases should be established.
Methods
We performed a case–control study of patients who were polymerase chain reaction–tested for COVID-19 (112 positive and 112 negative participants), recruited during the first wave (March 2020–May 2020) of the COVID-19 pandemic in Israel. Patients reported their symptoms and medical history by phone and rated their olfactory and gustatory abilities before and during their illness on a 1–10 scale.
Results
Changes in smell and taste occurred in 68% (95% CI, 60%–76%) and 72% (95% CI, 64%–80%) of positive patients, with odds ratios of 24 (range, 11–53) and 12 (range, 6–23), respectively. The ability to smell was decreased by 0.5 ± 1.5 in negatives and by 4.5 ± 3.6 in positives. A penalized logistic regression classifier based on 5 symptoms had 66% sensitivity, 97% specificity, and an area under the receiver operating characteristics curve (AUC) of 0.83 on a holdout set. A classifier based on degree of smell change was almost as good, with 66% sensitivity, 97% specificity, and 0.81 AUC. The predictive positive value of this classifier was 0.68, and the negative predictive value was 0.97.
Conclusions
Self-reported quantitative olfactory changes, either alone or combined with other symptoms, provide a specific tool for clinical diagnosis of COVID-19. A simple calculator for prioritizing COVID-19 laboratory testing is presented here.
Graphical Abstract
AMP-activated protein kinase (AMPK) is a regulator of energy balance at both the cellular and the whole-body levels. Direct activation of AMPK has been highlighted as a potential novel, and possibly ...safer, alternative to treat type II diabetes and obesity. In this study, we aimed to design and characterize novel peptides that mimic the αG region of the α2 AMPK catalytic domain to modulate its activity by inhibiting interactions between AMPK domains or other interacting proteins. The derived peptides were tested in vivo and in tissue culture. The computationally predicted structure of the free peptide with the addition of the myristoyl (Myr) or acetyl (Ac) moiety closely resembled the protein structure that it was designed to mimic. Myr-peptide and Ac-peptide activated AMPK in muscle cells and led to reduced adipose tissue weight, body weight, blood glucose levels, insulin levels, and insulin resistance index, as expected from AMPK activation. In addition, triglyceride, cholesterol, leptin, and adiponectin levels were also lower, suggesting increased adipose tissue breakdown, a result of AMPK activation. On the other hand, liver weight and liver lipid content increased due to fat retention. We could not find an elevated pAMPK:AMPK ratio in the liver in vivo or in hepatocytes ex vivo, suggesting that the peptide does not lead to AMPK activation in hepatocytes. The finding that an AMPK-derived peptide leads to the activation of AMPK in muscle cells and in adipose tissue and leads to reduced glucose levels in obese mice, but to fat accumulation in the liver, demonstrates the differential effect of AMPK modulation in various tissues.
Taste GPCRs and their ligands Dubovski, Nitzan; Fierro, Fabrizio; Margulis, Eitan ...
Progress in molecular biology and translational science,
2022, Letnik:
193, Številka:
1
Journal Article
Recenzirano
Taste GPCRs are expressed in taste buds on the tongue and play a key role in food choice and consumption. They are also expressed extra-orally, with various physiological roles that are currently ...under study. Unraveling the roles of these receptors relies on the knowledge of their ligands. Combining sensory, cell-based and computational approaches enabled the discovery of numerous agonists and several antagonists. Here we provide a short overview of taste receptor families, main recent methods for ligands discovery, and current sources of information about known ligands. The future directions that are likely to impact the taste GPCR field include focus on ligand interactions with naturally occurring polymorphisms, as well as harnessing the power of CryoEM and of multiple signaling readout techniques.
G protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets. GPCR ligands include odorants, tastants, and neurotransmitters and vary in ...size and properties. Dramatic chemical diversity may occur even among ligands of the same receptor. Our goal is to unravel the structural and chemical features that determine GPCRs’ promiscuity toward their ligands. We perform statistical analysis using more than 30 descriptors related to the sequence, physicochemical, structural, and energetic properties of the GPCR binding siteswe find that the chemical variability of antagonists significantly correlates with the binding site hydrophobicity and anticorrelates with the number of hydrogen bond donors in the binding site. The number of disulfide bridges in the extracellular region of a receptor anticorrelates with the range of molecular weights of its antagonists, highlighting the role of the entrance pathway in determining the size selectivity for GPCR antagonists. The predictive capability of the model is successfully validated using a separate set of GPCRs, using either X-ray structures or homology models.
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