Functional binding dynamics relevant to the evolution of zoonotic spillovers in endemic and emergent Betacoronavirus strains

Abstract

Comparative functional analysis of the dynamic interactions between various Betacoronavirus mutant strains and broadly utilized target proteins such as ACE2 and CD26, is crucial for a more complete understanding of zoonotic spillovers of viruses that cause diseases such as COVID-19. Here, we employ machine learning to replicated sets of nanosecond scale GPU accelerated molecular dynamics simulations to statistically compare and classify atom motions of these target proteins in both the presence and absence of different endemic and emergent strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. A multi-agent classifier successfully identified functional binding dynamics that are evolutionarily conserved from bat CoV-HKU4 to human endemic/emergent strains. Conserved dynamics regions of ACE2 involve both the N-terminal helices, as well as a region of more transient dynamics encompassing residues K353, Q325 and a novel motif AAQPFLL 386-92 that appears to coordinate their dynamic interactions with the viral RBD at N501. We also demonstrate that the functional evolution of Betacoronavirus zoonotic spillovers involving ACE2 interaction dynamics are likely pre-adapted from two precise and stable binding sites involving the viral bat progenitor strain’s interaction with CD26 at SAMLI 291-5 and SS 333-334. Our analyses further indicate that the human endemic strains hCoV-HKU1 and hCoV-OC43 have evolved more stable N-terminal helix interactions through enhancement of an interfacing loop region on the viral RBD, whereas the highly transmissible SARS-CoV-2 variants (B.1.1.7, B.1.351 and P.1) have evolved more stable viral binding via more focused interactions between the viral N501 and ACE2 K353 alone.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamics
• molecular evolution
• viral binding
• COVID 19

Acknowledgements

We acknowledge funding support from the National Science Foundation (NSF Award Number 2029885) and the National Institutes of Health (NIH grant GM116102). We also acknowledge the Nvidia Corporation for a hardware support grant.

Disclosure statement

The authors declare no competing interests.

Data availability statement

Structural models, images, movies and data sets for the post-processed molecular dynamics presented in this work are deposited at Zenodo CERN under the DOI 10.5281/zenodo.4702398 https://zenodo.org/record/4702398.

A movie file comparing SARS-CoV-2 RBD interaction with ACE2, in both wildtype and N501Y mutant strains is also available at https://youtu.be/ptn1_BBJi70.

Author contributions

PR, FC and GAB designed and executed the biological study. GAB designed the statistical methods and wrote computer code to implement the methods. PR, GAB, FC, AOH, and MLL interpreted the results and wrote the manuscript.