scholarly journals A Computational Approach for Protein-Protein Interactions of Bacterial Surface Layer Protein with Human Erb3 and αIIB-β3 Receptors

2021 ◽  
Vol 12 (1) ◽  
pp. 420-430
Keyword(s):  
Surface Layer ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Protein A ◽  
Computational Approach ◽  
Microbial Interactions ◽  
Protein Protein Interactions ◽  
Epithelial Surface ◽  
Surface Receptors ◽  
Surface Layer Protein

Host microbial interactions had significant factors in maintains homeostasis and immune-related activity. One such interaction made by Lactobacillus sp. with Surface layer proteins (Slps) had been studied through a computational approach. Erb3 and αIIB-β3, which are epithelial surface layer receptors, are subjected to interact with the Slp homology model. Both cell surface receptors were subjected to interact through computational docking, followed by molecular dynamics simulations through the coarse-grain method to explore the conformational stability. Through the implementation of the molecular docking for the surface layer protein A, we have shown the surface layer protein A, protein-protein interactions are higher in cellular receptors with epidermal growth factor receptor at an -34.45 ΔG and -51.19 ΔG through molecular docking with Erb3 and αIIB-β3. This study shows the unique interaction of Slp with the epithelial surface receptors like Erb3 and αIIB-β3, which are multipurpose applications in microbial-based drug therapeutics.

scholarly journals An Integrative Computational Approach for the Prediction of Human-Plasmodium Protein-Protein Interactions

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Kais Ghedira ◽  
Yosr Hamdi ◽  
Abir El Béji ◽  
Houcemeddine Othman
Keyword(s):  
Protein Interactions ◽  
Computational Approach ◽  
Protein Protein Interactions ◽  
Human Red Blood Cells ◽  
Pharmacological Targets ◽  
Host Pathogen ◽  
Human Proteins ◽  
Life Threatening ◽  
Similarity Method ◽  
Human Plasmodium

Host-pathogen molecular cross-talks are critical in determining the pathophysiology of a specific infection. Most of these cross-talks are mediated via protein-protein interactions between the host and the pathogen (HP-PPI). Thus, it is essential to know how some pathogens interact with their hosts to understand the mechanism of infections. Malaria is a life-threatening disease caused by an obligate intracellular parasite belonging to the Plasmodium genus, of which P. falciparum is the most prevalent. Several previous studies predicted human-plasmodium protein-protein interactions using computational methods have demonstrated their utility, accuracy, and efficiency to identify the interacting partners and therefore complementing experimental efforts to characterize host-pathogen interaction networks. To predict potential putative HP-PPIs, we use an integrative computational approach based on the combination of multiple OMICS-based methods including human red blood cells (RBC) and Plasmodium falciparum 3D7 strain expressed proteins, domain-domain based PPI, similarity of gene ontology terms, structure similarity method homology identification, and machine learning prediction. Our results reported a set of 716 protein interactions involving 302 human proteins and 130 Plasmodium proteins. This work provides a list of potential human-Plasmodium interacting proteins. These findings will contribute to better understand the mechanisms underlying the molecular determinism of malaria disease and potentially to identify candidate pharmacological targets.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

scholarly journals Determining rewiring effects of alternatively spliced isoforms on protein-protein interactions using a computational approach

2018 ◽  
Author(s):  
Oleksandr Narykov ◽  
Nathan Johnson ◽  
Dmitry Korkin
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Computational Approach ◽  
Superior Performance ◽  
Large Set ◽  
Protein Protein Interactions ◽  
Specific Expression ◽  
Alternatively Spliced ◽  
Specific Regulation

AbstractThe critical role of alternative splicing (AS) in cell functioning has recently become apparent, whether in studying tissue-or cell-specific regulation, or understanding molecular mechanisms governing a complex disorder. Studying the rewiring, or edgetic, effects of alternatively spliced isoforms on protein interactome can provide system-wide insights into these questions. Unfortunately, high-throughput experiments for such studies are expensive and time-consuming, hence the need to develop an in-silico approach. Here, we formulated the problem of characterization the edgetic effects of AS on protein-protein interactions (PPIs) as a binary classification problem and introduced a first computational approach to solve it. We first developed a supervised feature-based classifier that benefited from the traditional features describing a PPI, the problem-specific features that characterized the difference between the reference and alternative isoforms, and a novel domain interaction potential that allowed pinpointing the domains employed during a specific PPI. We then expanded this approach by including a large set of unlabeled interactomics data and developing a semi-supervised learning method. Our method called AS-IN (Alternatively Splicing INteraction prediction) Tool was compared with the state-of-the-art PPI prediction tools and showed a superior performance, achieving 0.92 in precision and recall. We demonstrated the utility of AS-IN Tool by applying it to the transcriptomic data obtained from the brain and liver tissues of a healthy mouse and western diet fed mouse that developed type two diabetes. We showed that the edgetic effects of differentially expressed transcripts associated with the disease condition are system-wide and unlikely to be detected by looking only at the gene-specific expression levels.

scholarly journals Lactococcus lactis Delivery of Surface Layer Protein A Protects Mice from Colitis by Re-Setting Host Immune Repertoire

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1098
Author(s):  
Ananta Prasad Arukha ◽  
Christian Furlan Freguia ◽  
Meerambika Mishra ◽  
Jyoti K. Jha ◽  
Subhashinie Kariyawasam ◽  
...  
Keyword(s):  
Surface Layer ◽  
Lactococcus Lactis ◽  
Oral Delivery ◽  
Protein A ◽  
The United States ◽  
Protective Mechanisms ◽  
Surface Layer Protein ◽  
Murine Colitis ◽  
Control And Prevention ◽  
Human Dendritic Cells

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn’s disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Lactobacillus acidophilus that possesses anti-inflammatory properties to mitigate murine colitis. Herein, we expressed SlpA in a clinically relevant, food-grade Lactococcus lactis to further investigate and characterize the protective mechanisms of the actions of SlpA. Oral administration of SlpA-expressing L. lactis (R110) mitigated the symptoms of murine colitis. Oral delivery of R110 resulted in a higher expression of IL-27 by myeloid cells, with a synchronous increase in IL-10 and cMAF in T cells. Consistent with murine studies, human dendritic cells exposed to R110 showed exquisite differential gene regulation, including IL-27 transcription, suggesting a shared mechanism between the two species, hence positioning R110 as potentially effective at treating colitis in humans.

scholarly journals Structure of PDE3A–SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jie Chen ◽  
Nan Liu ◽  
Yinpin Huang ◽  
Yuanxun Wang ◽  
Yuxing Sun ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Catalytic Domain ◽  
Cultured Cells ◽  
Hydrophobic Interactions ◽  
Complex Structure ◽  
Protein A ◽  
Protein Translation ◽  
Protein Protein Interactions ◽  
Cryo Electron Microscopy ◽  
Apoptosis Inducer

AbstractMolecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus “gluing” the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts.

scholarly journals Surface Layer Protein A Expressed in Clostridioides difficile DJNS06-36 Possesses an Encephalitogenic Mimotope of Myelin Basic Protein

2020 ◽  
Vol 9 (1) ◽  
pp. 34
Author(s):  
John E. Mindur ◽  
Sudhir K. Yadav ◽  
Naoko Ito ◽  
Mitsutoshi Senoh ◽  
Haru Kato ◽  
...  
Keyword(s):  
T Cells ◽  
Surface Layer ◽  
Amino Acid ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Demyelinating Disease ◽  
Protein A ◽  
Enteric Bacteria ◽  
Surface Layer Protein ◽  
Clostridioides Difficile

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that migration of Th1 and Th17 cells specific for enteric bacteria from the gut to the CNS may lead to the initiation and/or exacerbation of autoimmune diseases including MS. Human leukocyte antigen (HLA)-DR15 is an MHC class II (MHCII) haplotype highly associated with the development of MS that contains the two HLA-DRB* genes, DRB1*1501 (DR2b) and DRB5*0101 (DR2a). To identify enteric bacteria which harbor antigenic epitopes that activate myelin-specific T cells and drive CNS inflammation, we screened for enteric bacteria which express cross-reactive epitopes (‘mimotopes’) of an immunodominant myelin basic protein 89–98 (MBP89-98) epitope. Based on known MHCII HLA-DR2a amino acid binding motifs and cultivation with splenic T cells isolated from MBP-T cell receptor (TCR)/DR2a transgenic (Tg) mice, we discovered that a certain variant of surface layer protein A (SLPA), which is expressed by a subtype of Clostridioides difficile, contains an amino acid sequence that activates MBP89-98-reactive T cells. Furthermore, activation of MBP-specific T cells by SLPA upon active immunization induced experimental autoimmune encephalomyelitis (EAE) in MBP-TCR/DR2a Tg mice. This study suggests that a unique strain of C. difficile possesses an encephalitogenic mimotope of MBP that activates autoreactive, myelin-specific T cells.

scholarly journals Molecular Docking and Dynamics Simulation of a Screening Library from Life Chemicals Database for Potential Protein-Protein Interactions (PPIs) Inhibitors against SARS-CoV-2 Spike Protein

2021 ◽  
pp. 74-84
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Salam Waheed Ahjel ◽  
Ahmed Fadhil Hashim ◽  
Ali Mahmood Rayshan
Keyword(s):  
Molecular Docking ◽  
Receptor Binding ◽  
Protein Interactions ◽  
Binding Domain ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Protein Protein Interactions ◽  
Molecular Docking And Dynamics

The ongoing pandemic of coronavirus 2 represents a major challenge for global public health authorities. Coronavirus disease 2019 can be fatal especially in elderly people and those with comorbidities. Currently, several vaccines against coronavirus 2 are under application in multiple countries with emergency use authorization. In the same time, many vaccine candidates are under development and assessment. It is worth noting that the design of some of these vaccines depends on the expression of receptor binding domain for viral spike protein to induce host immunity. As such, blocking the spike protein interface with antibodies, peptides or small molecular compounds can impede the ability of coronavirus 2 to invade host cells by intervention with interactions between viral spike protein and cellular angiotensin converting enzyme 2. In this virtual screening study, we have used predictive webservers, molecular docking and dynamics simulation to evaluate the ability of 3000 compounds to interact with interface residues of spike protein receptor binding domain. This library of chemicals was focused by Life Chemicals as potential protein-protein interactions inhibitor. Here, we report that hit compound 7, with IUPAC name of 3‐cyclohexyl‐N‐(4‐{[(1R,9R) ‐6‐oxo‐7,11‐ diazatricyclo [7.3.1.02,7] trideca‐2,4‐dien‐11‐yl] sulfonyl} phenyl) propenamide, may have the capacity to interact with interface of receptor binding domain for viral spike protein and thereby reduce cellular entry of the virus. However, in vitro and in vivo assessments may be required to validate these virtual findings.

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