A recently identified variant of SARS-CoV-2 virus, known as the United Kingdom (UK) variant (lineage B.1.1.7), has an N501Y mutation on its spike protein. SARS-CoV-2 spike protein binds with angiotensin-converting enzyme 2 (ACE2), a key protein for the viral entry into the host cells. Here, we report an efficient computational approach, including the simple energy minimizations and binding free energy calculations, starting from an experimental structure of the binding complex along with experimental calibration of the calculated binding free energies, to rapidly and reliably predict the binding affinities of the N501Y mutant with human ACE2 (hACE2) and recently reported miniprotein and hACE2 decoy (CTC-445.2) drug candidates. It has been demonstrated that the N501Y mutation markedly increases the ACE2-spike protein binding affinity (Kd) from 22 to 0.44 nM, which could partially explain why the UK variant is more infectious. The miniproteins are predicted to have ∼10,000-to 100,000-fold diminished binding affinities with the N501Y mutant, creating a need for design of novel therapeutic candidates to overcome the N501Y mutation-induced drug resistance. The N501Y mutation is also predicted to decrease the binding affinity of a hACE2 decoy (CTC-445.2) binding with the spike protein by ∼200-fold. This convenient computational approach along with experimental calibration may be similarly used in the future to predict the binding affinities of potential new variants of the spike protein. :.
|Number of pages||7|
|Journal||Journal of Physical Chemistry B|
|State||Published - May 6 2021|
Bibliographical noteFunding Information:
This work was supported in part by the funding of the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health (P20 GM130456 and T32 DA016176). The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on their Lipscomb Compute Cluster and their NVIDIA V100 nodes.
© 2021 American Chemical Society. All rights reserved.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry