PDF(Pubmed)
Abstract：
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.
摘要：
SARS-CoV-2刺突蛋白含有功能上重要的脂肪酸（FA）结合位点，在其他一些冠状病毒中也发现了这种病毒，例如SARS-CoV和MERS-CoV。亚油酸（LA）对FA位点的占据通过将尖峰锁定在感染性较低的构象中来降低感染性。这里,我们使用动态-非平衡分子动力学（D-NEMD）模拟来比较尖峰变体对LA去除的变构响应。D-NEMD模拟表明，FA位点与蛋白质的其他功能区域偶联，例如受体结合基序(RBM)，N端域（NTD），弗林蛋白酶切割位点，和融合肽周围的区域。D-NEMD模拟还鉴定了将FA位点连接到这些功能区域的变构网络。野生型穗与四种变体(Alpha，Delta,Deltaplus,和OmicronBA.1）表明，这些变体对LA去除的反应显着不同。Alpha上与FA位点的变构连接通常与野生型蛋白上的相似，除了RBM和S71-R78地区，显示与FA网站的链接较弱。相比之下,Omicron是最不同的变体，在RBM上表现出显著差异，NTD,V622-L629和弗林蛋白酶切割位点。变构调制的这些差异可能具有功能相关性，可能影响传播性和毒力。LA对SARS-CoV-2变体影响的实验比较，包括新兴的变体，是有保证的。
