D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect

The crown of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is constituted by its spike (S) glycoprotein. S protein mediates the SARS-CoV-2 entry into the host cells. The “fusion core” of the heptad repeat 1 (HR1) on S plays a crucial role in the virus infectivity, as it is part of...

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Main Authors: Romina Oliva, Abdul Rajjak Shaikh, Andrea Petta, Anna Vangone, Luigi Cavallo
Format: Article
Language:English
Published: MDPI AG 2021-04-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/26/9/2622
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author Romina Oliva
Abdul Rajjak Shaikh
Andrea Petta
Anna Vangone
Luigi Cavallo
author_facet Romina Oliva
Abdul Rajjak Shaikh
Andrea Petta
Anna Vangone
Luigi Cavallo
author_sort Romina Oliva
collection DOAJ
description The crown of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is constituted by its spike (S) glycoprotein. S protein mediates the SARS-CoV-2 entry into the host cells. The “fusion core” of the heptad repeat 1 (HR1) on S plays a crucial role in the virus infectivity, as it is part of a key membrane fusion architecture. While SARS-CoV-2 was becoming a global threat, scientists have been accumulating data on the virus at an impressive pace, both in terms of genomic sequences and of three-dimensional structures. On 15 February 2021, from the SARS-CoV-2 genomic sequences in the GISAID resource, we collected 415,673 complete S protein sequences and identified all the mutations occurring in the HR1 fusion core. This is a 21-residue segment, which, in the post-fusion conformation of the protein, gives many strong interactions with the heptad repeat 2, bringing viral and cellular membranes in proximity for fusion. We investigated the frequency and structural effect of novel mutations accumulated over time in such a crucial region for the virus infectivity. Three mutations were quite frequent, occurring in over 0.1% of the total sequences. These were S929T, D936Y, and S949F, all in the N-terminal half of the HR1 fusion core segment and particularly spread in Europe and USA. The most frequent of them, D936Y, was present in 17% of sequences from Finland and 12% of sequences from Sweden. In the post-fusion conformation of the unmutated S protein, D936 is involved in an inter-monomer salt bridge with R1185. We investigated the effect of the D936Y mutation on the pre-fusion and post-fusion state of the protein by using molecular dynamics, showing how it especially affects the latter one.
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spelling doaj.art-34132273ab3d457abe1d8a6a0359427a2023-11-21T17:55:58ZengMDPI AGMolecules1420-30492021-04-01269262210.3390/molecules26092622D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural EffectRomina Oliva0Abdul Rajjak Shaikh1Andrea Petta2Anna Vangone3Luigi Cavallo4Department of Sciences and Technologies, University Parthenope of Naples, Centro Direzionale Isola C4, I-80143 Naples, ItalyKaust Catalysis Center, Physical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi ArabiaDipartimento di Informatica ed Applicazioni, University of Salerno, Via Papa Paolo Giovanni II, I-84048 Fisciano, ItalyRoche Innovation Center Munich, Pharma Research and Early Development, Large Molecule Research, Nonnenwald 2, 82377 Penzberg, GermanyKaust Catalysis Center, Physical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi ArabiaThe crown of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is constituted by its spike (S) glycoprotein. S protein mediates the SARS-CoV-2 entry into the host cells. The “fusion core” of the heptad repeat 1 (HR1) on S plays a crucial role in the virus infectivity, as it is part of a key membrane fusion architecture. While SARS-CoV-2 was becoming a global threat, scientists have been accumulating data on the virus at an impressive pace, both in terms of genomic sequences and of three-dimensional structures. On 15 February 2021, from the SARS-CoV-2 genomic sequences in the GISAID resource, we collected 415,673 complete S protein sequences and identified all the mutations occurring in the HR1 fusion core. This is a 21-residue segment, which, in the post-fusion conformation of the protein, gives many strong interactions with the heptad repeat 2, bringing viral and cellular membranes in proximity for fusion. We investigated the frequency and structural effect of novel mutations accumulated over time in such a crucial region for the virus infectivity. Three mutations were quite frequent, occurring in over 0.1% of the total sequences. These were S929T, D936Y, and S949F, all in the N-terminal half of the HR1 fusion core segment and particularly spread in Europe and USA. The most frequent of them, D936Y, was present in 17% of sequences from Finland and 12% of sequences from Sweden. In the post-fusion conformation of the unmutated S protein, D936 is involved in an inter-monomer salt bridge with R1185. We investigated the effect of the D936Y mutation on the pre-fusion and post-fusion state of the protein by using molecular dynamics, showing how it especially affects the latter one.https://www.mdpi.com/1420-3049/26/9/2622COVID-19spike proteinmutationsmolecular dynamicsinfectivity
spellingShingle Romina Oliva
Abdul Rajjak Shaikh
Andrea Petta
Anna Vangone
Luigi Cavallo
D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
Molecules
COVID-19
spike protein
mutations
molecular dynamics
infectivity
title D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
title_full D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
title_fullStr D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
title_full_unstemmed D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
title_short D936Y and Other Mutations in the Fusion Core of the SARS-CoV-2 Spike Protein Heptad Repeat 1: Frequency, Geographical Distribution, and Structural Effect
title_sort d936y and other mutations in the fusion core of the sars cov 2 spike protein heptad repeat 1 frequency geographical distribution and structural effect
topic COVID-19
spike protein
mutations
molecular dynamics
infectivity
url https://www.mdpi.com/1420-3049/26/9/2622
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