首页|SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid

SARS-CoV-2 spike variants differ in their allosteric responses to linoleic acid

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The SARS-CoV-2 spike protein contains a functionally important fatty acid(FA)binding site,which is also found in some other coronaviruses,e.g.SARS-CoV and MERS-CoV.The occupancy of the FA site by linoleic acid(LA)reduces infectivity by'locking'the spike in a less infectious conformation.Here,we use dynamical-nonequilibrium molecular dynamics(D-NEMD)simulations to compare the allosteric responses of spike variants to LA removal.D-NEMD simulations show that the FA site is coupled to other functional regions of the protein,e.g.the receptor-binding motif(RBM),N-terminal domain(NTD),furin cleavage site,and regions surrounding the fusion peptide.D-NEMD simulations also identify the allosteric networks connecting the FA site to these functional regions.The comparison between the wild-type spike and four variants(Alpha,Delta,Delta plus,and Omicron BA.1)shows that the variants differ significantly in their responses to LA removal.The allosteric connections to the FA site on Alpha are generally similar to those on the wild-type protein,with the exception of the RBM and the S71-R78 region,which show a weaker link to the FA site.In contrast,Omicron is the most different variant,exhibiting significant differences in the RBM,NTD,V622-L629,and furin cleavage site.These differences in the allosteric modulation may be of functional relevance,potentially affecting transmissibility and virulence.Experimental comparison of the effects of LA on SARS-CoV-2 variants,including emerging variants,is warranted.

SARS-CoV-2 spikeallosteric modulationD-NEMD simulationsfatty acid binding siteSARS-CoV-2 variants

A.Sofia F.Oliveira、Deborah K.Shoemark、Andrew D.Davidson、Imre Berger、Christiane Schaffitzel、Adrian J.Mulholland

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School of Chemistry,Centre for Computational Chemistry,University of Bristol,Bristol BS8 1TS,UK

School of Chemistry,University of Bristol,Bristol BS8 1TS,UK

School of Biochemistry,University of Bristol,Bristol BS8 1TD,UK

School of Cellular and Molecular Medicine,University of Bristol,University Walk,Bristol BS8 1TD,UK

School of Chemistry,Max Planck Bristol Centre for Minimal Biology,Bristol BS8 1TS,UK

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Engineering and Physical Sciences Research CouncilEngineering and Physical Sciences Research CouncilBiotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research CouncilEuropean Research Council(ERC)under the European Union's Horizon 2020 research and innovation programmeBrisSynBio,a BBSRC/EPSRC Synthetic Biology Research Centre

EPSRCEP/M022609/1BBSRCBB/R016445/1101021207BB/L01386X/1

2023

10.1093/jmcb/mjad021

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.15(3)
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