Developing a Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein Model in a Viral Membrane.

Hyeonuk Woo,Sang-Jun Park,Min Sun Yeom,Maham Tanveer,Nathan R Kern,Wonpil Im,Yiwei Cao,Tristan I Croll,Jumin Lee,Taeyong Park,Chaok Seok,Yeol Kyo Choi

doi:10.1021/acs.jpcb.0c04553

Abstract

This technical study describes all-atom modeling and simulation of a fully glycosylated full-length SARS-CoV-2 spike (S) protein in a viral membrane. First, starting from PDB: 6VSB and 6VXX, full-length S protein structures were modeled using template-based modeling, de-novo protein structure prediction, and loop modeling techniques in GALAXY modeling suite. Then, using the recently determined most occupied glycoforms, 22 N-glycans and 1 O-glycan of each monomer were modeled using Glycan Reader & Modeler in CHARMM-GUI. These fully glycosylated full-length S protein model structures were assessed and further refined against the low-resolution data in their respective experimental maps using ISOLDE. We then used CHARMM-GUI Membrane Builder to place the S proteins in a viral membrane and performed all-atom molecular dynamics simulations. All structures are available in CHARMM-GUI COVID-19 Archive (http://www.charmm-gui.org/docs/archive/covid19) so that researchers can use these models to carry out innovative and novel modeling and simulation research for the prevention and treatment of COVID-19.

Highlights

The ongoing COVID-19 pandemic is affecting the whole world seriously, with nearly 5 million reported infections and over 300,000 deaths as of May, 2020
The S1 subunit contains the signal peptide (SP), N terminal domain (NTD), and receptor binding domain (RBD) that bind to human angiotensin converting enzyme-2 (hACE2)
We report all-atom fully-glycosylated, fulllength S protein structure models that can be used for further molecular modeling and simulation studies

Summary

■ INTRODUCTION

The ongoing COVID-19 pandemic is affecting the whole world seriously, with nearly 5 million reported infections and over 300,000 deaths as of May, 2020. Starting from PDB: 6VSB and 6VXX, the structures were generated by combined endeavors of protein structure prediction of missing residues and domains, in silico glycosylation on all potential sites, and refinement based on experimental density maps. Researchers can use the PDB files available in COVID-19 Archive and Glycan Reader & Modeler[25−27] in CHARMM-GUI to modify the glycan sequences and build structures according to their own needs. While both 6VSB and 6VXX were of unusually high quality for their resolutions (perhaps a testament to the continuous improvement of modelling standards), there were some issues that without correction could lead to serious local structural problems in an equilibrium simulation An example of this is the loop-spanning residues 673−686 that are missing in 6VSB (Figure 3).

■ CONCLUDING DISCUSSION

■ ACKNOWLEDGMENTS

■ REFERENCES