ACE2 Binding Affinity
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved..
The strength of binding between human angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of viral spike protein plays a role in the transmissibility of the SARS-CoV-2 virus. In this study we focus on a subset of RBD mutations that have been frequently observed in infected individuals and probe binding affinity changes to ACE2 using surface plasmon resonance (SPR) measurements and free energy perturbation (FEP) calculations. Our SPR results are largely in accord with previous studies but discrepancies do arise due to differences in experimental methods and to protocol differences even when a single method is used. Overall, we find that FEP performance is superior to that of other computational approaches examined as determined by agreement with experiment and, in particular, by its ability to identify stabilizing mutations. Moreover, the calculations successfully predict the observed cooperative stabilization of binding by the Q498R N501Y double mutant present in Omicron variants and offer a physical explanation for the underlying mechanism. Overall, our results suggest that despite the significant computational cost, FEP calculations may offer an effective strategy to understand the effects of interfacial mutations on protein-protein binding affinities and, hence, in a variety of practical applications such as the optimization of neutralizing antibodies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:435 |
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| Enthalten in: |
Journal of molecular biology - 435(2023), 15 vom: 01. Aug., Seite 168187 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sergeeva, Alina P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.07.2023 Date Revised 21.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jmb.2023.168187 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Sergeeva, Alina P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Free Energy Perturbation Calculations of Mutation Effects on SARS-CoV-2 RBD::ACE2 Binding Affinity |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a The strength of binding between human angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of viral spike protein plays a role in the transmissibility of the SARS-CoV-2 virus. In this study we focus on a subset of RBD mutations that have been frequently observed in infected individuals and probe binding affinity changes to ACE2 using surface plasmon resonance (SPR) measurements and free energy perturbation (FEP) calculations. Our SPR results are largely in accord with previous studies but discrepancies do arise due to differences in experimental methods and to protocol differences even when a single method is used. Overall, we find that FEP performance is superior to that of other computational approaches examined as determined by agreement with experiment and, in particular, by its ability to identify stabilizing mutations. Moreover, the calculations successfully predict the observed cooperative stabilization of binding by the Q498R N501Y double mutant present in Omicron variants and offer a physical explanation for the underlying mechanism. Overall, our results suggest that despite the significant computational cost, FEP calculations may offer an effective strategy to understand the effects of interfacial mutations on protein-protein binding affinities and, hence, in a variety of practical applications such as the optimization of neutralizing antibodies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a FEP | |
| 650 | 4 | |a SPR | |
| 650 | 4 | |a ddG prediction | |
| 650 | 4 | |a protein–protein interactions | |
| 650 | 4 | |a receptor binding domain and angiotensin converting enzyme 2 | |
| 650 | 7 | |a Angiotensin-Converting Enzyme 2 |2 NLM | |
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| 650 | 7 | |a spike protein, SARS-CoV-2 |2 NLM | |
| 650 | 7 | |a Spike Glycoprotein, Coronavirus |2 NLM | |
| 700 | 1 | |a Katsamba, Phinikoula S |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Junzhuo |e verfasserin |4 aut | |
| 700 | 1 | |a Sampson, Jared M |e verfasserin |4 aut | |
| 700 | 1 | |a Bahna, Fabiana |e verfasserin |4 aut | |
| 700 | 1 | |a Mannepalli, Seetha |e verfasserin |4 aut | |
| 700 | 1 | |a Morano, Nicholas C |e verfasserin |4 aut | |
| 700 | 1 | |a Shapiro, Lawrence |e verfasserin |4 aut | |
| 700 | 1 | |a Friesner, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a Honig, Barry |e verfasserin |4 aut | |
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