Bitter taste receptors establish a stable binding affinity with the SARS-CoV-2-spike 1 protein akin to ACE2.

COVID-19 is caused by the highly contagious SARS-CoV-2 virus, which originated in Wuhan, China, resulting in the highest worldwide mortality rate. Gustatory dysfunction is common among individuals infected with the Wild-type Wuhan strain. However, there are no reported cases of gustatory dysfunction among patients infected with the mutant delta variant. The reason behind this remains elusive to date. This in-silico-based study aims to unravel this clinical factor by evaluating the overall binding affinity of predominant bitter taste receptors associated with gustatory function (T2R-4, 10, 14, 19, 31, 38, 43, and 46) with the Receptor Binding Domain (RBD) of spike 1 (S1) protein of Wuhan (Wild)/delta-SARS-CoV-2 (mut1-T478K; mut2-E484K) variants. Based on docking and MM/PBSA free binding energy scores, the Wild RBD showed a stronger interaction with T2R-46 compared to the ACE2 protein. However, both delta variant mutants (mut1 and mut2) could not establish a stronger binding affinity with bitter taste receptor proteins, except for T2R-43 against mut1. In conclusion, the delta variants could not establish a better binding affinity with bitter taste receptors, contradicting the Wild variant that determines the severity of gustatory dysfunction among patients exposed to the delta and Wild SARS-CoV-2 variants. The study's inference also proposes T2R-46 as an alternate binding receptor target for RBD-S1 of Wild SARS-CoV-2, augmenting its virulence in all functional organs with compromised α-gustducin interaction and bitter sensitization. This in-silico-based study needs further wet-lab-based validation for a better understanding of the role of T2R-46-based viral entry in the human host.Communicated by Ramaswamy H. Sarma.

Evaluation of the antiglycating potential of thymoquinone and its interaction with BSA.

Thymoquinone (TQ) is a bioactive component of medicinal plant, Nigella sativa. It has been identified as promising anti-inflammatory and anti-analgesic properties. In the present study, the TQ has been investigated for physiological interaction as well as binding properties with serum albumin and their thermodynamic parameters at different temperatures. Glycation process was checked with the measurement of fructosamine content, carbonyl content and total advanced glycated end products. The aggregation of amyloid ß-structure was measured with Thioflavin-T and the secondary structure of BSA was observed by circular dichroism (CD) in glycated and thermal treated samples. The results indicate that the TQ showed binding interaction (both static and dynamic) with BSA (Kb= 18.31 × 107 M-1 at 293 K) and suppression of glycated products. The glycation-induced and thermal aggregation were prevented and the secondary structure of BSA was maintained. Therefore, these findings suggest that TQ may be used for a therapeutic drug for antiglycation as well as anti-aggregation.Communicated by Ramaswamy H. Sarma.

Molecular docking analysis of hyperphosphorylated tau protein with compounds derived from Bacopa monnieri and Withania somnifera.

Tau protein, the major player in Alzheimer's disease forms neurofibrillary tangles in elderly people. Bramhi (Baccopa Monniera) is often used as an ayurvedic treatment for Alzheimer's disease. Therefore it is of interest to study the interaction of compounds derived from Baccopa with the Tau protein involved in tangle formation. We show that compounds such as bacopaside II, bacopaside XII, and nicotine showed optimal binding features with the R2 repeat domain of hyperphosphorylated tau protein for further consideration in the context of Alzheimer's disease (AD).

Risk association of BST2 gene variants with disease progression in HIV-1 infected Indian cohort.

Bone marrow stromal cell antigen 2 (BST2) is an interferon induced host restriction factor for HIV-1 that blocks the release of nascent virions from infected T cells. We aimed to characterize BST2 gene variants in HIV-1 positive individuals in Indian cohort and study the association of these variants with disease progression in long term non progressors (LTNPs) and progressors. Archived samples of 32 LTNPs, 17 progressors, and 78 controls were screened for BST2 gene polymorphisms using Sanger's sequencing method. Frequency distribution, survival analysis and bioinformatics tools were used to study the association of BST2 variants with disease progression. Eighteen variants of BST2 gene were observed in Indian cohort. Intronic SNP rs919267T/C (OR = 4.489 [0.8494-27.03], p = .04157) and exonic SNP rs13485C/G (OR = 3.887 [0.8262-25.56], p = .0488) were found to be significantly associated with disease progression. Also, rs13485C/C genotype in combination with rs919267C/T (OR = 9.406 [1.384-111], p = .0085) and rs145303329 Δ19bp (OR = 3.887 [0.826-25.5], p = .048) were found to be significantly associated with disease progression. 19 bp indel rs145303329 and its allele c.1-443_1-442insCGCCCCCAGAC[C/T]CAGGCCC from BST2 promoter also showed association with disease progression (OR = 12.97 [0.9731-850.5], p = .026). Docking of AP2 repressor with above allele showed the total binding energy of LTNPs and progressors to be -2581.42 kcal/mol and -3563.27/-3562.84 kcal/mol respectively. We have identified the novel association of three BST2 gene SNPs; rs919267, rs13485 and indel rs145303329 from Indian cohort to be associated with the risk of HIV-1 disease progression for the first time.

Molecular characterization of inhibin-A: Structure and expression analysis in Clarias batrachus.

The inhibins are disulphide-linked heterodimeric glycoproteins that belong to the TGFß superfamily. Inhibins have been well studied in mammals but the information about their structure and function is very limited in lower vertebrates. The aim of the present study was to characterize inhibin-A and to understand its receptor binding interaction, and to evaluate its biological function in Clarias batrachus. Structure prediction of inhibin-A revealed two glycosylation sites on inhibin-α (Asp262 and Asn334). Docking of inhibin-A with its receptor; betaglycan and Act RIIA showed that residues Ser321, Gly324 and Leu325 of inhibin-α are involved in high affinity binding with betaglycan while inhibin-ßA bound to Act RIIA by forming hydrogen bonds. The mRNA transcript analysis of various tissues indicated the presence of higher to moderate expression of inhibin-α and inhibin-ßA in the gonads and the extra-gonadal tissues. Further, stage specific expression showed decreased levels of inhibin-α in the gonads during the annual reproductive cycles. Inhibin-ßA, activin-ßB and Act RIIA increased in the brain during spawning while FSHr increased in the gonads during the preparatory phase. Our study provides molecular, structural and functional insights of inhibin-A for the first time in C. batrachus.

Seminal role of deletion of amino acid residues in H1-S2 and S-loop regions in eukaryotic ß-tubulin investigated from docking and dynamics perspective.

Tubulin is the fundamental unit of microtubules. It is reported to effect different functions like cell division, chromosomal segregation, motility and intracellular transportation. α- and ß-tubulin associate laterally and longitudinally to form protofilaments. Both the subunits are structurally identical to each other except for the deletions reported in H1-S2 and S loop regions in eukaryotic ß-tubulin. These deletions mimic the ancestral tubulin protein named Latest Common FtsZ-Tubulin Ancestor (LCFTA) with a shorter S-loop region resulting in weak dimerization. However, in eukaryotic beta tubulin, the significance of this shorter region remains elusive till date. The main objective of this study was to model variants of beta tubulin (ßmut1, ßmut2 and ßmut3) with inserts that lengthened the loop, and to compare them with the native α- and ß-subunits to understand their biological significance. Further, one more mutant was modeled with the intention of understanding the counter effect of additional deletion of amino acid residues from both H1-S2 and S-loop regions; this mutant was designated as ßmut4. Our study confirms that the insertion of amino acid residues considerably increases the protein-protein interactions in ßmut1-ßmut1, ßmut2-ßmut2 and ßmut3-ßmut3 compared to their native ß-subunit. Similarly, the binding affinity of GTP also increases in ßmut2 and ßmut3 as compared to the wild type. However, these deletions result in decreased protein-protein and ligand interactions in wild beta tubulin and ßmut4, as compared to ßmut1, ßmut2,and ßmut3. Therefore, we conclude here that residual inserts in the H1-S2 and S loop sub segments bring about conformational changes in regions critically involved in lateral interactions and in the nucleotide binding site, thus altering the binding affinities between the dimers and the ligands. Regarding the biological importance of such deletions in wild beta tubulin, these deletions result in flexible M-loop leading to weak protein-protein interaction. This could be an adaptive feature playing a crucial role in protofilament dissociation during GTP hydrolysis, because of weak dimerization.