Jeffery Klauda, an associate professor in the Department of Chemical and Biomolecular Engineering, is working on multiple projects to help combat COVID-19 at the cellular level.
What are the problems you're trying to solve?
Our computational lab is focused on several aspects related to COVID-19 infection utilizing high performance computing resources at UMD (Deepthought2), co-share with Johns Hopkins (MARCC), resources at the National Institutes of Health, or national supercomputing resources (XSEDE). We are looking into the mechanism of the virus particle attaching to its human target protein and virus protein mutations that influence this attachment.
Another project is focusing on certain COVID-19-related proteins that appear to be important to the level of infection and how these can be controlled via potential inhibitors. Finally, we are aiming to better understand the reason that the COVID-19 infection can result in blood clotting and how to potentially develop a target therapy.
Can you provide a summary of your research projects?
Modeling COVID-19 attachment and important mutations: In April 2019, Mahdi Ghorbani, a Ph.D. student working in the Klauda lab, in collaboration with Dr. Bernie Brooks at the National Institutes of Health, started probing the mechanism of virus interaction with the human host. This is known to occur with the virus spike protein and its receptor binding domain (RBD) attaching to the human angiotensin converter enzyme (ACE2) protein. This RBD/ACE2 complex was simulated with full atomistic detail to compare to a past coronavirus and how the RBD of COVID-19 has changed to increase its affinity to us humans. We have quantified the important parts of the protein sequence to stabilizing the RBD/ACE2 interface and also investigated important known mutations for different COVID-19 strains. Some of these RBD mutations appear to result in an increase attraction of the virus to the host’s ACE2. It is yet to be discovered if infections with strains that have increased RBD/ACE2 interaction have worse prognosis.
Modeling dimerization of COVID-19 accessory proteins: This work is that of a recently awarded NSF EAGER grant to support collaborative research between Dr. Min-Kang Hsieh (UMD) and Dr. Bryan Berger’s lab at the University of Virginia. We are investigating how two proteins (ORF7a and ORF7b) either self-associate or associate with human proteins during infection. This association has been shown important toward the virulence of the disease. We are using computational tools to predict the structure and mechanism for the association of these proteins, where wet lab measurements are done in Dr. Berger’s lab.
Modeling the COVID-19 virial membrane and associated blood clotting: One of the serious complications from this virus is the development of blood clots. Our research is to better understand what aspect of the infection (the virus particle and/or infected cells) is causing the development of blood clots. The lipid composition of the virial envelope and infected cells is unknown and we are collaborating with Dr. David Goodlett (UMB) to obtain the lipid composition so that our lab can simulate its structure and determine how this might be related to infection-associated blood clotting. Moreover, we are collaborating with Dr. Sergei Sukharev’s lab in the Department of Biology to develop potential peptide shields that will prevent blood clotting. This work will focus on the blood clotting cascade and relation to exposed negatively charged-lipids on the outer cell surface.
How will this research help us fight the COVID-19 virus?
The overall goal of this research is to focus on ways to potentially treat those infected by this virus. Our work on RBD/ACE2 interaction can be used by others to design potential protein interface inhibitors. The project involving the association of COVID-19 accessory proteins will involve predicting potential peptide inhibitors of protein association that might provide a treatment for those infected. Similarly, research on virus-associated blood clotting will provide the fundamentals to develop ways to develop protective shields and prevent the clotting cascade that has resulted in many deaths from COVID-19.
Are there any plans for future research on this topic?
We have only touched the surface in our basic understanding of this virus. This and other research will be important towards developing a treatment and infection-preventative strategies. Our future goal will be to focus on potential treatment approaches to inhibiting accessory protein association and blood clotting. Ultimately, pharmaceutical companies will develop vaccines to reduce the chances of infection, but treatment options will still be required for those who become infected because they did not receive the vaccine, or the vaccine is not fully effective in preventing infection.