Understanding how to stop the novel coronavirus (COVID-19) from attacking cells and the immune system is a challenge that scientists are facing around the world as they race against the clock to create treatments and vaccines to fight the pandemic. According to new research from Pomona College, Caltech and DePaul University, one key to unlocking that puzzle may be in understanding the effect of metal ions on a pair of the novel coronavirus’ proteins—the virus’s main protease and the protein in the virus’s spikes.
In an article published in the Journal of Inorganic Biochemistry, Pomona College Professor of Chemistry Roberto A. Garza-López, DePaul University Professor of Chemical Physics John Kozak and Caltech Professor of Chemistry Harry B. Gray are sharing their findings in order to contribute to the worldwide effort to end the pandemic. Titled “Structural stability of the SARS-CoV-2 main protease: Can metal ions affect function?” the article was picked to be part of a special issue to celebrate the publication’s 50th anniversary.
Using computational techniques employed in Garza-López’s lab and experimental results obtained 20 years ago in Gray’s lab, the team began working in February on the properties of these two pieces of the novel coronavirus, both of which are important to the virus’s normal functioning. The virus uses its spike protein to attach itself to human cells. Then, like a pair of molecular scissors, the protease activates the virus by cutting its large polyproteins into smaller segments that can attack human cells.
Through almost daily research via Zoom discussions and computational modeling, the researchers proposed that certain complexes of copper and cobalt might inhibit the normal functioning of those two vital pieces of the virus’s protein. Inhibiting either the attachment of the virus or the catalytic action that activates it could prevent the virus from wreaking havoc on individual cells and, ultimately, the immune system.
“The purpose of knowing the mechanism to inhibit the SARS-CoVid-2 virus is to guide the design of COVID-19-specific therapeutics and vaccines suitable for mass immunization,” says Garza-López. “Drug design will focus on the ability to stop the novel coronavirus before it attaches to human cells or reproduces itself. That’s why we believe the contribution of our last two papers and this one that was just accepted will be able to say something about this mechanism.”
John H. Dawson and Greeshma Nair, editor-in-chief and publisher of the Journal of Inorganic Biochemistry, respectively, wrote to “congratulate the authors on this important research. We are pleased that the Journal of Inorganic Biochemistry could provide a suitable platform to capture these new developments in COVID-19 research. We hope that this will be a significant contribution towards the concerted efforts worldwide in tackling this pandemic.”
In early February, a team of Chinese scientists shared the crystal structure of the main coronavirus protease, protein 6LU7, in the Protein Data Bank, an open-access digital data resource available to scientists around the world, with the aim of promoting scientific discovery. One day after 6LU7 was deposited by the Chinese team, Garza-López pulled the data to begin his work.
“I visualize the protein, and we go piece by piece and identify different pockets in which we can stop either the attachment of the virus or the enzyme catalysis that is responsible for the polyprotein that will inject the machinery into the cell to replicate and destroy the immune system,” he explains. “Many simulations are performed daily in my lab to get the right inhibiting mechanism.”
As COVID-19 swept the world and turned into a global pandemic, Garza-López and Gray took to Zoom to conduct daily research meetings. Garza-López has also overseen 13 student researchers this summer, including both students at Pomona College and high school students in Pomona’s summer enrichment program, known as PAYS (Pomona College Academy for Youth Success). “Computational research has not slowed down, in spite of spending considerable time at improving my teaching online and having five PAYS students and eight Pomona College undergraduates this summer,” he says, adding that the students have had all the means necessary to continue their work uninterrupted without having to meet in person or put each other at risk.
“The new coronavirus that causes the COVID-19 illness is unique. It’s very easy to transmit, which makes it more dangerous than the other coronaviruses, especially when it mutates and improves its efficiency,” says Garza-López. “We are interested in how the spike protein structure behaves and its points of weakness as well as the recent D614G mutation that has increased its efficiency of transmission 10 times.”
A previous article by the trio of researchers titled “Funneled Angle Landscapes for Helical Proteins,” also published in the Journal of Inorganic Biochemistry, as well as one titled “Unfolding Cytochromes c-b562 and Rd apo b562,” recently accepted for publication in the same journal, laid the groundwork for their current research.
Garza-López, Gray and Kozak have a long history of studying proteins, how they interact, how they fold and unfold, how they react with certain metallic elements. Prior to their interest in coronaviruses, the team was working on the folding and unfolding of the proteins azurin and cytochrome c’ and energy transfer in special molecules called dendrimers. The improper unfolding of proteins has been linked to cancers and other diseases such as Alzheimer’s and Parkinson’s.
Gray, known internationally for his groundbreaking work with metalloproteins, is the founding director of the Beckman Institute at Caltech and is considered one of the “pioneers of electron transfer in proteins,” says Garza-López. Gray was the 2005 Robbins Lecturer at Pomona College, giving a series of lectures titled: “The Currents of Life: Electron Flow Through Biological Molecules.”
Garza-López is a theoretical/computational physical chemist who has published more than 40 peer-reviewed journal articles in areas of statistical thermodynamics, stochastic processes, random walks, diffusion-controlled reactions on fractal and Euclidean surfaces, protein folding and molecular docking, as well as molecular mechanics and dynamics. He has taught chemistry at Pomona College since 1992.