1. Evolution of the <scp>SARS‐CoV</scp> ‐2 proteome in three dimensions (3D) during the first 6 months of the <scp>COVID</scp> ‐19 pandemic
- Author
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Charlotte Labrie-Cleary, Jitendra Singh, Steven Arnold, Andrew Sam, Mark Dresel, Luz Helena Alfaro Alvarado, Rebecca Roberts, Emily Fingar, Jennifer Jiang, Paul Craig, Jean Baum, Eddy Arnold, Christine Zardecki, Grace Brannigan, Julia R. Koeppe, Elizabeth M Hennen, Alan Trudeau, Joseph H Lubin, Thejasvi Venkatachalam, Jonathan K. Williams, Kevin Catalfano, Stephen K. Burley, Brian P. Hudson, Isaac Paredes, Sagar D. Khare, Yana Bromberg, Katherine See, Evan Lenkeit, Shuchismita Dutta, J. Steen Hoyer, Erika McCarthy, Michael J. Pikaart, Santiago Soto Zapata, Jenna Currier, Stephanie Laporte, Jay A. Tischfield, Siobain Duffy, Britney Dyszel, Maria Voigt, Changpeng Lu, Bonnie L. Hall, Jesse Sandberg, Kailey Martin, Aaliyah Khan, Stephen A. Mills, Sophia Staggers, Allison Rupert, Elliott M Dolan, Vidur Sarma, Lindsey Whitmore, Helen Zheng, Ashish Duvvuru, David S. Goodsell, Michael Kirsch, Melanie Ortiz-Alvarez de la Campa, Ali A Khan, Matthew Benedek, Francesc X. Ruiz, John D. Westbrook, Marilyn Orellana, Lingjun Xie, Zhuofan Shen, Baleigh Wheeler, and Brea Tinsley
- Subjects
Proteome ,databases ,Viral protein ,coronavirus ,Computational biology ,pandemics ,Biology ,medicine.disease_cause ,Biochemistry ,Article ,Virus ,SARS‐CoV‐2 ,Protein structure ,COVID‐19 ,Structural Biology ,Molecular evolution ,evolution ,medicine ,Humans ,Prospective Studies ,molecular ,Amino Acids ,Molecular Biology ,Research Articles ,chemistry.chemical_classification ,SARS-CoV-2 ,Drug discovery ,COVID-19 ,Robustness (evolution) ,computer.file_format ,Protein Data Bank ,Amino acid ,viral proteins ,chemistry ,protein ,computer ,Function (biology) ,Research Article - Abstract
Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and 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.
- Published
- 2021
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