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biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.29.361261


The recent COVID-19 pandemic has brought about a surge of crowd-sourced initiatives aimed at simulating the proteins of the SARS-CoV-2 virus. A bottleneck currently exists in translating these simulations into tangible predictions that can be leveraged for pharmacological studies. Here we report on extensive electrostatic calculations done on an exascale simulation of the opening of the SARS-CoV-2 spike protein, performed by the Folding@home initiative. We compute the electric potential as the solution of the non-linear Poisson-Boltzmann equation using a parallel sharp numerical solver. The inherent multiple length scales present in the geometry and solution are reproduced using highly adaptive Octree grids. We analyze our results focusing on the electro-geometric properties of the receptor-binding domain and its vicinity. This work paves the way for a new class of hybrid computational and data-enabled approaches, where molecular dynamics simulations are combined with continuum modeling to produce high-fidelity computational measurements serving as a basis for protein bio-mechanism investigations.

biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.29.360479


Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19.

Carcinoma, Squamous Cell , Lymphopenia , COVID-19
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.09.12.294413


The coronavirus disease 2019 (COVID-19) is triggered by severe acute respiratory syndrome mediated by coronavirus 2 (SARS-CoV-2) infection and was declared by WHO as a major international public health concern. While worldwide efforts are being advanced towards vaccine development, the structural modeling of TCR-pMHC (T Cell Receptor-peptide-bound Major Histocompatibility Complex) regarding SARS-CoV-2 epitopes and the design of effective T cell vaccine based on these antigens are still unresolved. Here, we present both pMHC and TCR-pMHC interfaces to infer peptide epitopes of the SARS-CoV-2 proteins. Accordingly, significant TCR-pMHC templates (Z-value cutoff > 4) along with interatomic interactions within the SARS-CoV-2-derived hit peptides were clarified. Also, we applied the structural analysis of the hit peptides from different coronaviruses to highlight a feature of evolution in SARS-CoV-2, SARS-CoV, bat-CoV, and MERS-CoV. Peptide-protein flexible docking between each of the hit peptides and their corresponding MHC molecules were performed, and a multi-hit peptides vaccine against the S and N glycoprotein of SARS-CoV-2 was designed. Filtering pipelines including antigenicity, and also physiochemical properties of designed vaccine were then evaluated by different immunoinformatics tools. Finally, vaccine-structure modeling and immune simulation of the desired vaccine were performed aiming to create robust T cell immune responses. We anticipate that our design based on the T cell antigen epitopes and the frame of the immunoinformatics analysis could serve as valuable supports for the development of COVID-19 vaccine.

Respiratory Insufficiency , Coronavirus Infections , Severe Acute Respiratory Syndrome , COVID-19
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.04.16.043224


SARS-COV-2 and all other coronaviruses express its 3 prime genes by forming sub-genomic RNA. As the genome of these virus exist in RNA form, only by profiling the relative abundance of these sgRNAs, can the viral transcriptome be revealed. Utilizing publically available meta-transcriptomic data generated from patient samples, we were able to infer the viral transcriptome in vivo, which is distinct from the in vitro one derived from cell culture. Inter-sample diversity was also observed and a sample specific transcript was identified. By doing the same analysis to MERS and SARS data, we were able to compare the three in terms of transcription. Among the differences, SARS-COV-2 has significantly elevated expression of the Spike gene, which may contribute to its high transmissibility. HighlightsO_LIThe in vivo transcriptome of SARS-CoV-2 revealed by sgRNA profiling, for 25 patient samples around the globe. C_LIO_LIThe Spike protein expression is an order of magnitude higher in SARS-CoV-2 than MERS-CoV or SARS-CoV, possibly contributing to the virus elevated transmissibility. C_LIO_LIThe in vivo SARS-CoV-2 transcriptomes, as inferred from human patient data was distinct from the in vitro one derived from cell line culture, all the accessory genes were up-regulated in vivo, suggesting intricate expression regulation mechanism for the small viral genome. C_LI