Computational Analysis of SARS-CoV-2 Variants’ Binding with Vertebrate ACE2

Alyson Michael, Adithya Puninchittaya

Overview

Mentors: Alyson Michael, and Dr. Peter Faletra, Ph.D. This study explored the effect of changes in the spike protein of the Alpha, Beta, and Gamma variants of SARS-CoV-2 on the initial binding interactions with American mink (Neovison vison), brown rat (Rattus norvegicus), and domestic cat (Felis catus) ACE2 receptors. Coronavirus Disease 2019 (COVID-19) is an infectious respiratory disease caused by the coronavirus SARS-CoV-2. For cell infection to occur, the viral spike protein binds to the cellular angiotensin-converting enzyme II (ACE2) receptor-binding domain (RBD). Although other mammals are infected by SARS-CoV-2, it is not well understood how susceptibility to infection differs among SARS-CoV-2 variants. This study used the PRODIGY web server to investigate binding of variant spike proteins with ACE2 receptors from mammals. Results showed that, for the Alpha variant, Neovison vison has the most favorable ∆G of -16.3 kcal/mol, while Rattus norvegicus has the least favorable ∆G at -13.3 kcal/mol. For the Beta variant, Neovison vison has the most favorable binding affinity at -14.4 kcal/mol, while Felis catus has the least favorable ∆G at -12.9 kcal/mol. For the Gamma variant, Neovison vison has the most favorable binding energy at -15.2 kcal/mol, while Felis catus has the least favorable binding energy at -12.9 kcal/mol. This study employed both sequence and structural alignment of the spike protein RBDs of wild-type, Alpha, Beta, and Gamma variants to evaluate differences. Tertiary structural alignment of the spike protein RBDs suggests that the Beta variant most closely resembles the wild-type RBD structure while there was a large difference between the wild-type and Gamma variant. A sequence percent identity matrix of the variants’ spike protein RBDs suggests that the Alpha variant is most similar to wild-type, the Beta variant is most similar to the Alpha variant, the Gamma variant is most similar to the Beta variant. The Alpha variant is the most similar to the wild-type at 97.55%, with Beta and Gamma variants similar at 96.93% and 96.89%, respectively. In all cases, binding with the Alpha variant is more favorable than binding with the wild-type, likely due to the 30-40 additional interfacial contacts involved in binding with the Alpha, Beta, and Gamma variants. A more favorable ∆G was observed with the Gamma variant’s binding to Rattus norvegicus ACE2 in comparison to other variants.

From the student

I got to know about this program through a friend, and I applied immediately. I was so excited to make use of an opportunity to conduct authentic research on my own, in contrast to assisting in someone else's research. I was interested in conducting protein modeling research particularly because of its relevancy in this ongoing pandemic. Although I didn't know much about this subject matter, I wanted to try it. Over the course of the early summer, I took it upon myself to learn units of biology and chemistry and gain prerequisite knowledge for the research project. As I was learning, I contacted my mentor, Alyson Michael, with questions I had. After I gained some essential information, I was ready to begin protein modeling!

During the rest of the Summer, I was a part of a hybrid program at NHAS. Due to the portable nature of this type of research, I was able to conduct my research both at home and at the lab facilities (sometimes even in between!).

I am very grateful to my mentors Dr. Alyson Michael and Dr. Peter Faletra for assisting me through this research process and answering my never-ending questions. I would also like to thank Dr. Kelly Salmon for her guidance as well.

I enjoyed learning so much through this program and getting experience with important protein modeling software. I am even more excited to present my work at AJAS and learn more about other subjects at the conference, despite it being virtual.