To be prepared for a new challenge when another coronavirus jumps the species barrier to humans, we need to understand the virus, its host-interaction, possible drug-target sites, and the best antiviral strategies to mitigate it.
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Promising targets for the discovery and development of small-molecule antiviral agents is possible only when the complete viral genome fingerprint and the structural and functional information of the viral proteins are available.
Importantly, the sequence (and 3D structure) variation during the coronavirus 2019 (COVID-19) pandemic can be used to prioritize any potential drug targets using quantitative assessments of active site conservation.
In a recent bioRxiv* preprint publication, an interdisciplinary team of researchers reports how the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) proteome in 3D has evolved during the first six months of the COVID-19 pandemic. The team analyzed the three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank (PDB) and reported the evolution of these proteins.
In this comprehensive study, the researchers combined the viral genome sequence data assembled by GISAID during the first six months of the pandemic between late 2019 and June 25th, 2020. The researchers computed structural models in cases where experimentally-determined structures were not available.
The GISAID contains a wealth of experimental 3D structure information for SARS-CoV-2 and other coronavirus proteins available from the open-access Protein Data Bank.
Most of the work reported in the paper is initiated by research interns (undergraduates and one high school student) hosted virtually during the summer of 2020 by the Rutgers University, Institute for Quantitative Biomedicine (IQB), the Rutgers University RISE Program, and the US-funded RCSB Protein Data Bank headquartered at Rutgers.
The team developed, evaluated, and refined the methods used in this research study during an online Boot Camp, supervised by IQB graduate students, postdoctoral fellows, and RCSB Protein Data Bank scientific staff, all of whom served as mentors in the Boot Camp.
The team carried out multiple sequence alignments, constructed phylogenetic trees, computed 3D structural models of viral proteins, visualized 3D structures, and analyzed the structural, functional, and energetic consequences of SARS-CoV-2 protein amino acid substitutions identified during the first six months of the pandemic.
The researchers analyzed more than 48,000 viral proteome sequences, archived by GISAID. They analyzed the spatial locations, the chemical properties, and the structural and energetic impacts of the observed amino acid changes in these sequences.
In this study, they show that the analyses of SARS-CoV-2 genome sequences documented that every one of the 29 study proteins underwent amino acid changes. This is in comparison to the original reference sequence during the first six months of the pandemic.
They computed structural models for every unique sequence variant and found that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores.
They found that the protein cores were more frequently affected in conservative changes when compared to the surface/boundary changes of the protein.
They found infrequent substitutions in the active sites and the protein-protein interfaces. Most of the substitutions were non-conservative, and appear to have arisen from single or double nucleotide changes in the RNA genome.
Also, the calculations of the energetics showed that the thermodynamic stability of the proteome after substitutions follows a universal bi-Gaussian distribution. The team believes that because most of the viral genomes archived by GISAID were obtained from samples provided by infected individuals, the viruses and hence the viral proteins are functional and capable of causing disease in humans.
The researchers also present detailed results for six drug discovery targets. They also show four structural proteins comprising the virion, highlighting substitutions that can impact the protein structure, the enzyme activity, and the functional interfaces.
Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.”
The study presents the viral proteome evolution during the first six months of the COVID-19 pandemic.
For researchers wishing to perform further computational and experimental studies, the computed 3D structural models and energetics results are made freely available under Creative Commons license. This may enable drug hunting teams to anticipate potential sources of drug resistance during selection for candidates slated for in vitro preclinical development studies, the researchers write.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic; Joseph H. Lubin, Christine Zardecki, Elliott M. Dolan, Changpeng Lu, Zhuofan Shen, Shuchismita Dutta, John D. Westbrook, Brian P. Hudson, David S. Goodsell, Jonathan K. Williams, Maria Voigt, Vidur Sarma, Lingjun Xie, Thejasvi Venkatachalam, Steven Arnold, Luz Helena Alfaro Alvarado, Kevin Catalfano, Aaliyah Khan, Erika McCarthy, Sophia Staggers, Brea Tinsley, Alan Trudeau, Jitendra Singh, Lindsey Whitmore, Helen Zheng, Matthew Benedek, Jenna Currier, Mark Dresel, Ashish Duvvuru, Britney Dyszel, Emily Fingar, Elizabeth M. Hennen, Michael Kirsch, Ali A. Khan, Charlotte Labrie-Cleary, Stephanie Laporte, Evan Lenkeit, Kailey Martin, Marilyn Orellana, Melanie Ortiz-Alvarez de la Campa, Isaac Paredes, Baleigh Wheeler, Allison Rupert, Andrew Sam, Katherine See, Santiago Soto Zapata, Paul A. Craig, Bonnie L. Hall, Jennifer Jiang, Julia R. Koeppe, Stephen A. Mills, Michael J. Pikaart, Rebecca Roberts, Yana Bromberg, J. Steen Hoyer, Siobain Duffy, Jay Tischfield, Francesc X. Ruiz, Eddy Arnold, Jean Baum, Jesse Sandberg, Grace Brannigan, Sagar D. Khare, Stephen K. Burley bioRxiv 2020.12.01.406637; doi: https://doi.org/10.1101/2020.12.01.406637