scholarly journals A Comprehensive Computer Aided Vaccine Design Approach to Propose a Multi-Epitopes Subunit Vaccine against Genus Klebsiella Using Pan-Genomics, Reverse Vaccinology, and Biophysical Techniques

Vaccines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1087
Author(s):  
Khaled S. Allemailem
Keyword(s):  
Molecular Dynamics ◽  
Binding Free Energy ◽  
Water Soluble ◽  
Dynamics Simulation ◽  
Reverse Vaccinology ◽  
World Health ◽  
Potential Core ◽  
The Core ◽  
Core Proteins ◽  
Core Proteome

Klebsiella is a genus of nosocomial bacterial pathogens and is placed in the most critical list of World Health Organization (WHO) for development of novel therapeutics. The pathogens of the genus are associated with high mortality and morbidity. Owing to their strong resistance profile against different classes of antibiotics and nonavailability of a licensed vaccine, urgent efforts are required to develop a novel vaccine candidate that can tackle all pathogenic species of the Klebsiella genus. The present study aims to design a broad-spectrum vaccine against all species of the Klebsiella genus with objectives to identify the core proteome of pathogen species, prioritize potential core vaccine proteins, analyze immunoinformatics of the vaccine proteins, construct a multi-epitopes vaccine, and provide its biophysical analysis. Herein, we investigated all reference species of the genus to reveal their core proteome. The core proteins were then subjected to multiple reverse vaccinology checks that are mandatory for the prioritization of potential vaccine candidates. Two proteins (TonB-dependent siderophore receptor and siderophore enterobactin receptor FepA) were found to fulfill all vaccine parameters. Both these proteins harbor several potent B-cell-derived T-cell epitopes that are antigenic, nonallergic, nontoxic, virulent, water soluble, IFN-γ producer, and efficient binder of DRB*0101 allele. The selected epitopes were modeled into a multi-epitope peptide comprising linkers and Cholera Toxin B adjuvant. For docking with innate immune and MHC receptors and afterward molecular dynamics simulations and binding free energy analysis, the vaccine structure was modeled for tertiary structure and refined for structural errors. To assess the binding affinity and presentation of the designed vaccine construct, binding mode and interactions analysis were performed using molecular docking and molecular dynamics simulation techniques. These biophysical approaches illustrated the vaccine as a good binder to the immune receptors and revealed robust interactions energies. The vaccine sequence was further translated to nucleotide sequence and cloned into an appropriate vector for expressing it at high rate in Escherichia coli K12 strain. In addition, the vaccine was illustrated to generate a good level of primary, secondary, and tertiary immune responses, proving good immunogenicity of the vaccine. Based on the reported results, the vaccine can be a good candidate to be evaluated for effectiveness in wet laboratory validation studies.

scholarly journals EpitoCore: mining conserved epitope vaccine candidates in the core proteome of multiple bacteria strains

2019 ◽  
Author(s):  
T.S. Fiuza ◽  
J.P.M.S. Lima ◽  
G.A. de Souza
Keyword(s):  
Peptide Vaccine ◽  
Computational Prediction ◽  
Reverse Vaccinology ◽  
Automated Identification ◽  
Single Strain ◽  
Vaccine Candidates ◽  
The Core ◽  
Core Proteins ◽  
Conserved Genes ◽  
Core Proteome

ABSTRACTIn reverse vaccinology approaches, complete proteomes of bacteria are submitted to multiple computational prediction steps in order to filter proteins that are possible vaccine candidates. Most available tools perform such analysis only in a single strain, or a very limited number of strains. But the vast amount of genomic data had shown that most bacteria contain pangenomes, i.e. their genomic information contains core, conserved genes, and random accessory genes specific to each strain. Therefore, it is of the utmost importance to define core proteins, and also core epitopes, in reverse vaccinology methods. EpitoCore is a decision-tree pipeline developed to fulfill that need. It provides surfaceome prediction of proteins from related strains, defines clusters of core proteins within those, calculate the immunogenicity of such clusters, predicts epitopes for a given set of MHC alleles defined by the user, and then reports if epitopes are located extracellularly and if they are conserved among the core homologues. Pipeline performance is illustrated by mining peptide vaccine candidates in Mycobacterium avium hominissuis strains. From a total proteome of approximately 4,800 proteins per strain, EpitoCore mined 103 highly immunogenic core homologues located at cell surface, many of those related to virulence and drug resistance. Conserved epitopes identified among these homologues allows the users to define sets of peptides with potential to immunize the largest coverage of tested HLA alleles using peptide-based vaccines. Therefore, EpitoCore is able to provide automated identification of conserved epitopes in bacterial pangenomic datasets.

scholarly journals Identification of Cross-Protective Potential Antigens against PathogenicBrucellaspp. through Combining Pan-Genome Analysis with Reverse Vaccinology

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Yasmin Hisham ◽  
Yaqoub Ashhab
Keyword(s):  
Brucella Melitensis ◽  
Cell Epitope ◽  
Reverse Vaccinology ◽  
Pathogenic Species ◽  
The Core ◽  
Protective Antigens ◽  
Cumulative Score ◽  
Core Proteins ◽  
Associated Proteins ◽  
Core Proteome

Brucellosis is a zoonotic infectious disease caused by bacteria of the genusBrucella.Brucella melitensis,Brucella abortus, andBrucella suisare the most pathogenic species of this genus causing the majority of human and domestic animal brucellosis. There is a need to develop a safe and potent subunit vaccine to overcome the serious drawbacks of the live attenuatedBrucellavaccines. The aim of this work was to discover antigen candidates conserved among the three pathogenic species. In this study, we employed a reverse vaccinology strategy to compute the core proteome of 90 completed genomes: 55B. melitensis, 17B. abortus, and 18B. suis. The core proteome was analyzed by a metasubcellular localization prediction pipeline to identify surface-associated proteins. The identified proteins were thoroughly analyzed using variousin silicotools to obtain the most potential protective antigens. The number of core proteins obtained from analyzing the 90 proteomes was 1939 proteins. The surface-associated proteins were 177. The number of potential antigens was 87; those with adhesion score ≥ 0.5 were considered antigen with “high potential,” while those with a score of 0.4–0.5 were considered antigens with “intermediate potential.” According to a cumulative score derived from protein antigenicity, density of MHC-I and MHC-II epitopes, MHC allele coverage, and B-cell epitope density scores, a final list of 34 potential antigens was obtained. Remarkably, most of the 34 proteins are associated with bacterial adhesion, invasion, evasion, and adaptation to the hostile intracellular environment of macrophages which is adjusted to depriveBrucellaof required nutrients. Our results provide a manageable list of potential protective antigens for developing a potent vaccine against brucellosis. Moreover, our elaborated analysis can provide further insights into novelBrucellavirulence factors. Our next step is to test some of these antigens using an appropriate antigen delivery system.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

scholarly journals Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3018 ◽  
Author(s):  
Gao Tu ◽  
Tingting Fu ◽  
Fengyuan Yang ◽  
Lixia Yao ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Computational Simulation ◽  
Critical Role ◽  
Dynamics Simulation ◽  
Peptide Docking ◽  
C Terminus ◽  
Free Energy Decomposition

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

scholarly journals Comparative Analysis of the Core Proteomes among the Pseudomonas Major Evolutionary Groups Reveals Species-Specific Adaptations for Pseudomonas aeruginosa and Pseudomonas chlororaphis

Diversity ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 289
Author(s):  
Marios Nikolaidis ◽  
Dimitris Mossialos ◽  
Stephen G. Oliver ◽  
Grigorios D. Amoutzias
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pseudomonas Syringae ◽  
Pseudomonas Stutzeri ◽  
Phylogenomic Analysis ◽  
Pseudomonas Chlororaphis ◽  
Phylogenetic Groups ◽  
The Core ◽  
Core Proteins ◽  
Core Proteome ◽  
Species Specific

The Pseudomonas genus includes many species living in diverse environments and hosts. It is important to understand which are the major evolutionary groups and what are the genomic/proteomic components they have in common or are unique. Towards this goal, we analyzed 494 complete Pseudomonas proteomes and identified 297 core-orthologues. The subsequent phylogenomic analysis revealed two well-defined species (Pseudomonas aeruginosa and Pseudomonas chlororaphis) and four wider phylogenetic groups (Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas syringae, Pseudomonas putida) with a sufficient number of proteomes. As expected, the genus-level core proteome was highly enriched for proteins involved in metabolism, translation, and transcription. In addition, between 39–70% of the core proteins in each group had a significant presence in each of all the other groups. Group-specific core proteins were also identified, with P. aeruginosa having the highest number of these and P. fluorescens having none. We identified several P. aeruginosa-specific core proteins (such as CntL, CntM, PlcB, Acp1, MucE, SrfA, Tse1, Tsi2, Tse3, and EsrC) that are known to play an important role in its pathogenicity. Finally, a holin family bacteriocin and a mitomycin-like biosynthetic protein were found to be core-specific for P. cholororaphis and we hypothesize that these proteins may confer a competitive advantage against other root-colonizers.

MOLECULAR MODELING OF THE INTERACTIONS BETWEEN HISTONE DEACETYLASE 8 AND INHIBITORS

2012 ◽  
Vol 11 (04) ◽  
pp. 907-924 ◽  
Author(s):  
DAWEI HUANG ◽  
XIAOHUI LI ◽  
ZHILONG XIU
Keyword(s):  
Molecular Dynamics ◽  
Histone Deacetylases ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Zinc Ion ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Domain Docking ◽  
Dynamics Simulations ◽  
Linker Domain

Inhibitors of histone deacetylases (HDACs) have become an attractive class of anticancer agent. To understand the interaction between HDAC8 and inhibitors, including "pan-" inhibitors that inhibit many HDACs isoforms and selective inhibitors with no linker domain, docking and molecular dynamics simulation were conducted. Docking results showed the presence of π-π interactions between "linkerless" inhibitors and the aromatic amino acid residues of HDAC8 in the active site. Binding between HDAC8 and inhibitors was also stabilized by hydrogen bond and hydrophobic interaction. In molecular dynamics simulations, the zinc ion was shown to coordinate one more atom of HDAC8-"linkerless" inhibitor complexes than HDAC8-"pan-" inhibitor complexes. Persistent hydrogen bonds also existed between Tyr306 of HDAC8 and some inhibitors. When inhibitors with large cap groups bound to the active pocket of HDAC8, Phe152 and Met274 shifted from their initial positions and the entrance of the active pocket became more open, resulting in the formation of sub-pocket. Hydrophobic interactions contributed most favorably to the binding free energy between HDAC8 and inhibitors. Lys33, Asp178, Asp267, Tyr306 and Leu308 of HDAC8 were favorable for binding with all inhibitors.

Molecular Dynamics Simulations of Nanocomposite Diamond-Like Carbon

2005 ◽  
Author(s):  
G. T. Gao ◽  
J. D. Schall ◽  
K. Van Workum ◽  
P. T. Mikulski ◽  
J. A. Harrison
Keyword(s):  
Molecular Dynamics ◽  
Elastic Constants ◽  
Simulation Method ◽  
Dynamics Simulation ◽  
Diamond Structure ◽  
The Core ◽  
Constant Tension ◽  
Simulation Results ◽  
Dynamics Simulations ◽  
Carbon Network

A constant tension and constant temperature molecular dynamics simulation method was used in the calculations of the elastic constants of the nanocomposite systems. The nanocomposite systems contain a core of sp3 diamond structure surrounded by an amorphous carbon network. The simulation results show that the elastic properties of nanocomposites of diamond-like carbons are closely related to the size of the sp3 diamond core; the bigger the core, the larger the elastic constants, and the system becomes more anisotropic.

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