The S protein has a very flexible stem that consists of two independent joints. The flexible motions of the S proteins enable the receptor binding domain to have different orientations and the most likely S protein configurations are capable of ACE2 binding. Credit: Dr. Yeolkyo Choi
Lehigh researchers quantify the specific interaction between the vein proteins of EARS-CoV-2 – the virus that causes COVID-19 – with the ACE2 receptors in human cells that may partially explain the high rate of infection compared to SARS-CoV-1.
Bioengineering researchers at Lehigh University has identified a previously unknown interaction between receptors in human cells and the spike, or ‘S’, protein of SARS-CoV-2, the virus that causes COVID-19. This new information may help in developing new strategies to block SARS-CoV-2 access to human cells.
X. Frank Zhang and Wonpil Im knew from recent studies that the interaction between the SARS-CoV-2 peak protein and angiotensin-converting enzyme 2 (ACE2) receptors in human cells is stronger than the interaction between the structurally identical ear protein of SARS-CoV -1, the virus that caused the outbreak of the SARS 2002-2004, and the same receptors.
“Our goal was to characterize SARS-CoV-2 and study the protein-protein interactions during its invasion into human cells to provide more insight into the mechanisms that enable this first step in its successful invasion process,” says Zhang, associate professor in Bioengineering and Mechanical Engineering and Mechanics in Lehigh.
Their findings appear in an article entitled “Biomechanical Characterization of SARS-CoV-2-Spike RBD and Human ACE2 Protein-Protein Interaction” in a special issue of Biophysical Journal, “Biophysicists Address Covid-19 Challenges I”, published mid-March. Additional authors include, from Lehigh University: Wenpeng Cao, Decheng Hou and Seonghan Kim in bioengineering; Chuqiao Dong in mechanical engineering and mechanics; and, from Lindsley F. Kimball Research Institute, New York Blood Center, Wanbo Tai and Lanying Du.
Using combined single-molecule force spectroscopy and molecular dynamics simulations, Zhang and Im’s teams were able to identify a previously unknown interaction between ACE2 glucans (sugar groups on the surface of proteins) and the SARS-CoV-2 peak. This interaction appears to be responsible for enhancing the virus-cell interaction. This may partly explain the higher infection rate of COVID-19 compared to the similar virus that caused the SARS outbreak of 2002-2004.
“We were surprised to discover that the specific interaction between ACE2 glucans and the SARS-CoV-2 ear protein makes the separation of the virus from cells so difficult,” says Im, who is a professor of bioengineering, computer science, chemistry . and biological sciences, as well as the Presidential Endowed Chair in Health, Science and Engineering in Lehigh.
To arrive at these findings, the team used Zhang’s innovative single-molecule detection technique and measured the release force of the protein-ACE2 receptor interaction. Use the all-atom molecular dynamics simulations of the complex system available in CHARMM GUI developed by Im, they then identified the detailed structural information in this interaction.
“After carefully removing all the ACE2 glucans and measuring the potency of the interaction, we saw that the strength of the SARS-CoV-2 spike-ACE2 interaction dropped back to levels similar to SARS-CoV-1, “says Zhang.
“It is possible that this newly discovered interaction with ACE2-glucans may be a contributing factor to the higher dose of COVID-19 than the structurally similar SARS-CoV-1, which has a weaker interaction,” says Zhang. “Our hope is that researchers can use this information to develop new strategies to identify, prevent, treat and vaccinate COVID-19.”
Reference: “Biomechanical Characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction” by Wenpeng Cao, Chuqiao Dong, Seonghan Kim, Decheng Hou, Wanbo Tai, Lanying Du, Wonpil Im and X. Frank Zhang, 17 February 2021, Biophysical Journal.
DOI: 10.1016 / j.bpj.2021.02.007