Generative artificial intelligence performs rudimentary structural biology modeling
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60 APPLIED LIFE SCIENCES↗
Engineering topics
Markosian, Christopher
Publications and source records attributed to Markosian, Christopher.
Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion
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60 APPLIED LIFE SCIENCES↗
Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection
Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662–C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662–C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662–C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.
59 BASIC BIOLOGICAL SCIENCES↗
Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain
Significance The COVID-19 pandemic has had an unprecedented impact. Although several vaccines have received emergency use authorization, demand has created enormous logistical challenges—including supply, access, and distribution—that justify research for alternative strategies. Phage are viruses that only infect bacteria and can be safely administered to humans. Here, as a proof-of-concept study, we demonstrate that aerosol vaccination with lung-targeted phage particles displaying short SARS-CoV-2 S protein epitopes and subcutaneous vaccination with targeted AAVP particles carrying the entire S protein gene both elicit systemic and specific immune responses in immunocompetent mice. Given their unique attributes, including sturdiness, simple-to-engineer platform, cost-effectiveness for rapid large-scale production, and stability at room temperature, these phage-based approaches may become attractive tools for COVID-19 vaccine development.
59 BASIC BIOLOGICAL SCIENCES↗
Targeting a cell surface vitamin D receptor on tumor-associated macrophages in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is an aggressive tumor with limited treatment options and poor prognosis. We applied the in vivo phage display technology to isolate peptides homing to the immunosuppressive cellular microenvironment of TNBC as a strategy for non-malignant target discovery. We identified a cyclic peptide (CSSTRESAC) that specifically binds to a vitamin D receptor, protein disulfide-isomerase A3 (PDIA3) expressed on the cell surface of tumor-associated macrophages (TAM), and targets breast cancer in syngeneic TNBC, non-TNBC xenograft, and transgenic mouse models. Systemic administration of CSSTRESAC to TNBC-bearing mice shifted the cytokine profile toward an antitumor immune response and delayed tumor growth. Moreover, CSSTRESAC enabled ligand-directed theranostic delivery to tumors and a mathematical model confirmed our experimental findings. Finally, in silico analysis showed PDIA3-expressing TAM in TNBC patients. This work uncovers a functional interplay between a cell surface vitamin D receptor in TAM and antitumor immune response that could be therapeutically exploited.
59 BASIC BIOLOGICAL SCIENCES↗
Analysis of impact metrics for the Protein Data Bank
Since 1971, the Protein Data Bank (PDB) archive has served as the single, global repository for open access to atomic-level data for biological macromolecules. The archive currently holds >140,000 structures (>1 billion atoms). These structures are the molecules of life found in all organisms. Knowing the 3D structure of a biological macromolecule is essential for understanding the molecule’s function, providing insights in health and disease, food and energy production, and other topics of concern to prosperity and sustainability. PDB data are freely and publicly available, without restrictions on usage. Through bibliometric and usage studies, we sought to determine the impact of the PDB across disciplines and demographics. Our analysis shows that even though research areas such as molecular biology and biochemistry account for the most usage, other fields are increasingly using PDB resources. PDB usage is seen across 150 disciplines in applied sciences, humanities, and social sciences. Data are also re-used and integrated with >400 resources. Our study identifies trends in PDB usage and documents its utility across research disciplines.
59 BASIC BIOLOGICAL SCIENCES↗