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31.
Protein-glycan recognition is often mediated by multivalent binding. These multivalent bindings can be further complicated by cooperative interactions between glycans and individual glycan binding subunits. Here we have demonstrated a nanocube-based lipid bilayer array capable of quantitatively elucidating binding dissociation constants, maximum binding capacity, and binding cooperativity in a high-throughput format. Taking cholera toxin B subunit (CTB) as a model cooperativity system, we studied both GM1 and GM1-like gangliosides binding to CTB. We confirmed the previously observed CTB-GM1 positive cooperativity. Surprisingly, we demonstrated fucosyl-GM1 has approximately 7 times higher CTB binding capacity than GM1. In order to explain this phenomenon, we hypothesized that the reduced binding cooperativity of fucosyl-GM1 caused the increased binding capacity. This was unintuitive, as GM1 exhibited higher binding avidity (16 times lower dissociation constant). We confirmed the hypothesis using a theoretical stepwise binding model of CTB. Moreover, by taking a mixture of fucosyl-GM1 and GM2, we observed the mild binding avidity fucosyl-GM1 activated GM2 receptors enhancing the binding capacity of the lipid bilayer surface. This was unexpected as GM2 receptors have negligible binding avidity in pure GM2 bilayers. These unexpected discoveries demonstrate the importance of binding cooperativity in multivalent binding mechanisms. Thus, quantitative analysis of multivalent protein-glycan interactions in heterogeneous glycan systems is of critical importance. Our user-friendly, robust, and high-throughput nanocube-based lipid bilayer array offers an attractive method for dissecting these complex mechanisms. 相似文献
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S. Siddalingappa Archana Sellappan Selvaraju B. Krishnan Binsila Arunachalam Arangasamy Stephen A. Krawetz 《Molecular reproduction and development》2019,86(11):1485-1504
Declining fertility rates in both human and animals is a cause for concern. While many of the infertility cases are due to known causes, idiopathic infertility is reported in 30% of the infertile couples. In such cases, 18% of the infertile males carry antisperm antibodies (ASAs). Such data are lacking in livestock, wherein 20–30% of the animals are being culled due to low fertility. In males, the blood–testis barrier (BTB) and biomolecules in the semen provide an immuno‐tolerant microenvironment for spermatozoa as they traverse the immunologic milieu of both the male and female reproductive tracts. For example, insults from environmental contaminants, infections and inflammatory conditions are likely to impact the immune privilege state of the testis and fertility. The female mucosal immune system can recognize allogenic spermatozoa‐specific proteins affecting sperm kinematics and sperm‐zona binding leading to immune infertility. Elucidating the functions and pathways of the immune regulatory molecules associated with fertilization are prerequisites for understanding their impact on fertility. An insight into biomolecules associated with spermatozoal immune tolerance may generate inputs to develop diagnostic tools and modulate fertility. High‐throughput sequencing technologies coupled with bioinformatics analyses provides a path forward to define the array of molecules influencing pregnancy outcome. This review discusses the seminal immune regulatory molecules from their origin in the testis until they traverse the uterine environment enabling fertilization and embryonic development. Well‐designed experiments and the identification of biomarkers may provide a pathway to understand the finer details of reproductive immunology that will afford personalized therapies. 相似文献
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Density functional theory (DFT) calculations and molecular dynamics (MD) simulations on the atomic level were performed on
three different substituted banana-shaped compounds derived from 1,3-phenylene bis[4-(4-n-hexyloxyphenyliminomethyl)benzoate]
(P-6-O-PIMB). The DFT studies were carried out on the isolated molecules, and in the MD simulations clusters were treated
with up to 64 monomers. The effect of polar substituents, such as chlorine and the nitro group, on the central 1,3-phenylene
unit of banana-shaped compounds was investigated. In particular, flexibility, polarity, electrostatic potential (ESP) group
charge distributions, B-factors, bending angles and molecular lengths were considered. The MD results were analysed by trajectories
of significant torsion angles as well as order parameters such as radial atom pair distribution functions g(r), orientational
correlation functions g(o), diffusion coefficients (D) and root mean square deviations (RMSD) values. The g(r) and g(o) values
show that a certain long range order is generated by the introduction of a NO2 group in the 2-position of the central 1,3-phenylene ring. In contrast, the chlorination at the 4 and 6 positions of the
central 1,3-phenylene unit decreases the long range order tendency by its perturbation effect on the conformations in such
molecules. Moreover, g(r) and g(o) values, as well as diffusion coefficients, show that in the NO2 substituted compound the formation of microphase areas is preferred. Finally, the aggregation effect in such compounds was
studied in a systematic way by a comparison of the conformational properties of the isolated molecules and the monomers in
the clusters.
Figure Molecular dynamics (MD) simulations on the aggregation behaviour of substituted banana-shaped compounds
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
37.
Visceral leishmaniasis (VL) caused by Leishmania donovani is a major parasitic disease prevalent in endemic regions of Bihar in India. In the absence of good chemotherapeutic options, there is a need to develop an effective vaccine against VL which should be dependent on the generation of a T helper type 1 (Th1) immune response. We have shown that soluble proteins from promastigote of a new clinical isolate of L. donovani (2001) ranging from 68 to 97.4 kDa (F2 fraction), induce Th1 responses in the peripheral blood mononuclear cells of cured Leishmania patients and hamsters and also showed significant prophylactic potential. To understand the nature of F2 proteins, it was further characterized using 2-DE, MALDI-TOF and MALDI-TOF/TOF-MS. In all, 63 spots were cut from a CBB stained gel for analysis and data was retrieved for 52 spots. A total of 33 proteins were identified including six hypothetical/unknown proteins. Major immunostimulatory proteins were identified as elongation factor-2, p45, heat shock protein (HSP)70, HSP83, aldolase, enolase, triosephosphate isomerase, protein disulfideisomerase and calreticulin. This study substantiates the usefulness of proteomics in characterizing a complex protein fraction (F2) map of soluble L. donovani promastigote antigen identified as Th1 stimulatory for its potential as vaccine targets against VL. 相似文献
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Anup S. Deshpande Sellappan Krishnan Malapati K. Janarthanam Bruce R. Maslin 《Nordic Journal of Botany》2019,37(4)
An annotated checklist of Senegalia Raf. and Vachellia Wight & Arn. taxa for the Indian subcontinent is presented, following the fragmentation and retypification of the former broadly defined genus Acacia Mill. The countries encompassed by this study include Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka. All indigenous species (and a few introductions) in this region previously referred to Acacia belong to Senegalia and Vachellia. All Acacia s.s. taxa are introduced (principally from Australia) and are not included in the study. There are 22 species of Senegalia (21 indigenous, 1 introduced; representing 23 taxa) and 21 species of Vachellia (12 indigenous, 9 introduced; representing 27 taxa) currently recognized for the subcontinent. The largest country, India, has most species. This checklist complements that which was recently provided for these genera in southeast Asia and China. Two names formerly recorded for the Indian subcontinent are excluded, namely, Senegalia intsia (L.) Maslin is a nomen confusum and Acacia pennata subsp. hainanensis (Hayata) I. C. Nielsen is now known to be restricted to southern China and Vietnam. Acacia eriantha Desv. is an unresolved name. The following new combinations are made herein: Senegalia tanjorensis (Ragup., Thoth. & A.Mahad.) A.S.Deshpande & Maslin, Vachellia campbellii (Arn.) A.S.Deshp., & Maslin and V. pseudowightii (Thoth.) A.S.Deshpande & Maslin. A lectotype has been selected for Acacia pennata var. canescens Graham ex Kurz (= Senegalia pennata (L.) Maslin). 相似文献
40.
Nazia Khatoon Rajan Kumar Pandey Rupal Ojha Veeranarayanan Surya Aathmanathan Muthukalingan Krishnan 《Journal of biomolecular structure & dynamics》2019,37(9):2381-2393
Visceral leishmaniasis (VL) is a deadly parasitic infection which affects poorest to poor population living in the endemic countries. Increasing resistant to existing drugs, disease burden and a significant number of deaths, necessitates the need for an effective vaccine to prevent the VL infection. This study employed a combinatorial approach to develop a multi-epitope subunit vaccine by exploiting Leishmania donovani membrane proteins. Cytotoxic T- and helper T-lymphocyte binding epitopes along with suitable adjuvant and linkers were joined together in a sequential manner to design the subunit vaccine. The occurrence of B-cell and IFN-γ inducing epitopes approves the ability of subunit vaccine to develop humoral and cell-mediated immune response. Physiochemical parameters of vaccine protein were also assessed followed by homology modeling, model refinement and validation. Moreover, disulfide engineering was performed for the increasing stability of the designed vaccine and molecular dynamics simulation was performed for the comparative stability purposes and to conform the geometric conformations. Further, molecular docking and molecular dynamics simulation study of a mutated and non-mutated subunit vaccine against TLR-4 immune receptor were performed and respective complex stability was determined. In silico cloning ensures the expression of designed vaccine in pET28a(+) expression vector. This study offers a cost-effective and time-saving way to design a novel immunogenic vaccine that could be used to prevent VL infection.
Communicated by Ramaswamy H. Sarma 相似文献