Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins

Abstract

During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.Having infected over a hundred thousand people in more than a hundred countries across the globe, the new coronavirus, SARS-CoV-2, has a major health and economic impact worldwide. With a genome of the new virus sequenced, scientists learned that this virus is closely related to other coronaviruses, such as SARS-CoV and MERS-CoV. This discovery, however, leads to other questions. How different are the proteins of SARS-CoV-2, its main functional building blocks, from those of SARS-CoV? Does the new virus target the same proteins in human cells as the known coronaviruses? Most importantly, can the currently developed SARS or MERS antiviral drug candidates or other promising compounds be used to treat the new infection? This study lays out the first 3D roadmap of SARS-CoV-2 viral proteins and their functional complexes, enabling scientists to answer the above questions. The roadmap can be used to streamline the search for new antivirals and vaccines.

Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2

“…Very recently, the Cryo-EM structure of the SARS-CoV-2 spike protein in the prefusion conformation has been determined [30]. The biophysical and structural evidence suggested that SARS-CoV-2 may bind ACE2 with a much higher affinity than SARS-CoV [30].Although it has been clear that SARS-CoV-2 infects human cells through the binding of the RBD domain to the human ACE2 receptor [30][31][32][33][34], the molecular mechanism of the binding between the RBD protein and the ACE2 receptor is still unknown. Many questions remain to be answered.…”

“…Although it has been clear that SARS-CoV-2 infects human cells through the binding of the RBD domain to the human ACE2 receptor [30][31][32][33][34], the molecular mechanism of the binding between the RBD protein and the ACE2 receptor is still unknown. Many questions remain to be answered.…”

Master Regulator Analysis of the SARS-CoV-2/Human Interactome

“…We obtained a recently generated interactome of all the physical interactions between SARS-CoV-2 and human proteins based on the work by Korkin and colleagues [26]. In brief, the interactome contains both virus-virus and virus-host protein-protein interactions based on structural interaction modeling and established experimental knowledge.…”

“…Coexpression-based networks [27] were generated using the corto algorithm with default parameters, freely available on the CRAN repository of R packages [28], using the SARS-CoV-2/human interactome proteins derived from [26] and the largest human lung RNA-Seq dataset available from the GTEX consortium, which was generated from 427 patients gene expression profiles [29]. In brief, corto calculates a coexpression network for each protein and then removes indirect interactions using Data Processing Inequality [30], which has been shown to provide a more robust readout of single protein abundance alone [31].…”

“…We obtained the most up-to-date specific SARS-CoV-2/human interactome from [26]. This network, which we represent in Figure 1, highlights the complex interaction between the 31 viral proteins (coded by a genome of roughly 30kb) and 94 human proteins, ranging from surface enzymes (ACE2) to RNA-processing proteins (DDX5) to mitochondrial constituents (BCL2) [49].…”