COSAM News Articles 2022 March Unveiling the molecular mechanisms of coronavirus infection

Unveiling the molecular mechanisms of coronavirus infection

Published: 03/23/2022

Auburn scientists are key partners in a large international collaboration to investigate why the current outbreak of coronavirus is so much more devastating than the early 2000’s outbreak.

A scientific paper published this week at the prestigious PNAS journal (https://www.pnas.org/doi/10.1073/pnas.2114397119), and co-authored by Auburn biophysicists, digs into the mechanics of viral infection. The study brought together scientists with different expertise from Germany, Spain, California, Washington, Illinois, and Alabama. The authors describe how proteins from the current outbreak of coronavirus are significantly more resilient to shear forces than proteins of coronavirus from past outbreaks. The finding suggests that the response to force application is part of the evolutionary target of these viruses. But why would that be the case?

Seven   types   of   coronaviruses   cause   human   respiratory infections, four of them cause the common cold and three of them led to epidemics: SARS-CoV-1 (2003 outbreak), MERS-CoV (2012 outbreak), and the current SARS-CoV-2. On their surface, coronaviruses have characteristic club-shaped spikes, which make them look like a crown, hence their name.  As the first step of infection, the spike proteins of the coronavirus need to bind to proteins at the cell surface. The subset of coronaviruses that cause severe acute respiratory syndrome (SARS) are known to bind to the angiotensin-converting enzyme-2 (ACE2), allowing the virus to enter our cells. As one can imagine, ACE2 is not on our cells to serve as anchor points for viruses. In fact, ACE2 is part of an important protein system that is crucial to keep our body’s blood pressure in check.

So, how can the group of coronaviruses that are responsible for SARS interact so well with ACE2? During virus replication many different processes that are known to cause variations of these viruses’ genetic code occur. Some of these variations, or mutations, are beneficial for the virus, some are not. When viruses quickly spread over a population, the chances for beneficial mutations significantly increase. In a nutshell, that is how viruses evolve. According to Prof. Bernardi, from the Biophysics Cluster of Auburn’s College of Sciences and Mathematics, “some of the desired characteristics of the new variants of a virus are quite obvious. For instance, escaping our immune system is a common one”. However, some others are not so obvious. “What we are observing is that evolution might have favored coronaviruses that not only bind more tightly to human proteins, but that can also stay bound in a turbulent environment, for instance, when you sneeze.”

At Auburn, Bernardi’s group took advantage of their graphical processing unit (GPU)-based supercomputer infrastructure to investigate, atom by atom, the molecular interaction between the SARS-CoV-1 and SARS-CoV-2 spike proteins with the human ACE2 protein. His collaborators in Germany looked at the same interactions using magnetic tweezers (Prof. Jan Lipfert) and atomic force microscopes (Prof. Hermann Gaub). At end they noticed that SARS-CoV-2 spike could withstand much higher force-loads than SARS-CoV-1. More specifically, they noticed that SARS-CoV-2 spike:ACE2 interaction has higher mechanical stability, larger binding free energy, and lower dissociation rate when compared to SARS-CoV-1, which helps to rationalize the different infection patterns of the two viruses.

Additionally, Bernardi’s group was able to construct an artificial SARS-CoV-1 spike protein with only a handful of mutations, which was able to withstand forces in the same range of the SARS-CoV-2 spike. Dr. Priscila Gomes, a postdoctoral fellow at Prof. Bernardi’s group at the Department of Physics at Auburn, says that “the study also shows how powerful computational biophysics methods have become, and how they can be used to predict biological effects, not only complementing experimental evidence”. According to Dr. Marcelo Melo, who was a visiting scientist at Auburn during part of the studies,  “the group is now developing artificial intelligence methods to predict how mutations on the surface of proteins might affect their mechanical stability”. The research done at Auburn will help guide the development of new vaccines and therapies, taking into account  the possible new variants of the virus.

image of proteins

The Computational Biophysics Group at Auburn uses state-of-the-art graphical processing units to investigate the interaction between the spike proteins of SARS coronaviruses and the human ACE2 receptor protein.

Rafael Bernardi

Prof. Rafael Bernardi (left) is an assistant professor of Physics at the College of Sciences and Mathematics. He is a member of Auburn’s Biophysics Cluster, and also of the NIH Center for Macromolecular Modeling and Bioinformatics. Dr. Priscila Gomes (right) is a postdoctoral fellow at the Computational Biophysics Group, which is led by Prof. Bernardi. Dr. Gomes received a dual PhD from the École Normale Supérieure de Cachan (France), and the Biophysics Institute of the Federal University of Rio de Janeiro (Brazil).

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