@article {Lubin2020.12.01.406637, author = {Joseph H. Lubin and Christine Zardecki and Elliott M. Dolan and Changpeng Lu and Zhuofan Shen and Shuchismita Dutta and John D. Westbrook and Brian P. Hudson and David S. Goodsell and Jonathan K. Williams and Maria Voigt and Vidur Sarma and Lingjun Xie and Thejasvi Venkatachalam and Steven Arnold and Luz Helena Alfaro Alvarado and Kevin Catalfano and Aaliyah Khan and Erika McCarthy and Sophia Staggers and Brea Tinsley and Alan Trudeau and Jitendra Singh and Lindsey Whitmore and Helen Zheng and Matthew Benedek and Jenna Currier and Mark Dresel and Ashish Duvvuru and Britney Dyszel and Emily Fingar and Elizabeth M. Hennen and Michael Kirsch and Ali A. Khan and Charlotte Labrie-Cleary and Stephanie Laporte and Evan Lenkeit and Kailey Martin and Marilyn Orellana and Melanie Ortiz-Alvarez de la Campa and Isaac Paredes and Baleigh Wheeler and Allison Rupert and Andrew Sam and Katherine See and Santiago Soto Zapata and Paul A. Craig and Bonnie L. Hall and Jennifer Jiang and Julia R. Koeppe and Stephen A. Mills and Michael J. Pikaart and Rebecca Roberts and Yana Bromberg and J. Steen Hoyer and Siobain Duffy and Jay Tischfield and Francesc X. Ruiz and Eddy Arnold and Jean Baum and Jesse Sandberg and Grace Brannigan and Sagar D. Khare and Stephen K. Burley}, title = {Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic}, elocation-id = {2020.12.01.406637}, year = {2020}, doi = {10.1101/2020.12.01.406637}, publisher = {Cold Spring Harbor Laboratory}, 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.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2020/12/01/2020.12.01.406637}, eprint = {https://www.biorxiv.org/content/early/2020/12/01/2020.12.01.406637.full.pdf}, journal = {bioRxiv} }