Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic


Joseph H. Lubin, Rutgers University–New Brunswick
Christine Zardecki, Rutgers University–New Brunswick
Elliott M. Dolan, Rutgers University–New Brunswick
Changpeng Lu, Rutgers University–New Brunswick
Zhuofan Shen, Rutgers University–New Brunswick
Shuchismita Dutta, Rutgers University–New Brunswick
John D. Westbrook, Rutgers University–New Brunswick
Brian P. Hudson, Rutgers University–New Brunswick
David S. Goodsell, Rutgers University–New Brunswick
Jonathan K. Williams, Rutgers University–New Brunswick
Maria Voigt, Rutgers University–New Brunswick
Vidur Sarma, Rutgers University–New Brunswick
Lingjun Xie, Rutgers University–New Brunswick
Thejasvi Venkatachalam, Rutgers University–New Brunswick
Steven Arnold, Rutgers University–New Brunswick
Luz Helena Alfaro Alvarado, Grinnell College
Kevin Catalfano, University of Notre Dame
Aaliyah Khan, University of Maryland, Baltimore County (UMBC)
Erika McCarthy, Stevens Institute of Technology
Sophia Staggers, Frostburg State University
Brea Tinsley, Youngstown State University
Alan Trudeau, University of Central Florida
Jitendra Singh, New York City College of Technology
Lindsey Whitmore, Howard University
Helen Zheng, Watchung Hills Regional High School
Matthew Benedek, Xavier University
Jenna Currier, Hope College
Mark Dresel, Rutgers University–New Brunswick
Ashish Duvvuru, Hope College
Britney Dyszel, Ursinus College
Emily Fingar, SUNY Oswego
Elizabeth M. Hennen, Roger Williams University
Michael Kirsch, SUNY Oswego
Ali A. Khan, SUNY Oswego
Charlotte Labrie-Cleary, SUNY Oswego
Stephanie Laporte, Brandeis University

Document Type


Publication Title

Proteins: Structure, Function and Bioinformatics

Publication Date



Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 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 isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein–protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. 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 potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein–protein and protein–nucleic acid 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.