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)redu...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.展开更多
基金supported by the funding from the Engineering and Physical Sciences Research Council(EPSRC,grant number EP/M022609/1)the Biotechnology and Biological Sciences Research Council(BBSRC+3 种基金grant number BB/R016445/1)the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation programme(grant agreement no.101021207,project information:PREDACTED)We thank BrisSynBio,a BBSRC/EPSRC Synthetic Biology Research Centre(grant number BB/L01386X/1)Oracle for Research for funding A.S.F.O.We also thank EPSRC via HECBioSim(https://www.hecbiosim.ac.uk/)for providing ARCHER/ARCHER2 time through a COVID-19 rapid response call.C.S.and I.B.are investigators of the Wellcome Trust(210701/Z/18/Z and 106115/Z/14/Z).
文摘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.
