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Journal article
Entropic Overcompensation of the N501Y Mutation on SARS-CoV-2 S Binding to ACE2
Journal of chemical information and modeling, v 63(2), pp 633-642
30 Dec 2022
PMID: 36584335
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein's receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [Prévost et al.
2021, 297, 101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on the enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Furthermore, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intraprotein root mean square fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y's ability to remodel the inter-residue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein-protein binding affinity is the degree to which fluctuations are distributed throughout the complex and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result in increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.
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Details
- Title
- Entropic Overcompensation of the N501Y Mutation on SARS-CoV-2 S Binding to ACE2
- Creators
- Natasha Gupta Vergara - Drexel UniversityMegan Gatchel - University of DelawareCameron F Abrams - Drexel University
- Publication Details
- Journal of chemical information and modeling, v 63(2), pp 633-642
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 10
- Grant note
- ACI-1548562 / National Science Foundation; National Science Foundation (NSF) 1949718 / NSF; National Science Foundation (NSF) P01 AI150471 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1949718 / Div Of Engineering Education and Centers; Directorate For Engineering; National Science Foundation (NSF); NSF - Directorate for Engineering (ENG)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000907830200001
- Scopus ID
- 2-s2.0-85145449921
- Other Identifier
- 991019455966004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Multidisciplinary
- Computer Science, Information Systems
- Computer Science, Interdisciplinary Applications