Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.
J Phys Chem B. 2021 Aug 19;125(32):9155-9167. doi: 10.1021/acs.jpcb.1c04871. Epub 2021 Aug 9.
A marker for the severeness and disease progress of COVID-19 is overexpression of serum amyloid A (SAA) to levels that in other diseases are associated with a risk for SAA amyloidosis. To understand whether SAA amyloidosis could also be a long-term risk of SARS-CoV-2 infections, we have used long all-atom molecular dynamic simulations to study the effect of a SARS-CoV-2 protein segment on SAA amyloid formation. Sampling over 40 μs, we find that the presence of the nine-residue segment SK9, located at the C-terminus of the envelope protein, increases the propensity for SAA fibril formation by three mechanisms: it reduces the stability of the lipid-transporting hexamer shifting the equilibrium toward monomers, it increases the frequency of aggregation-prone configurations in the resulting chains, and it raises the stability of SAA fibrils. Our results therefore suggest that SAA amyloidosis and related pathologies may be a long-term risk of SARS-CoV-2 infections.
COVID-19 严重程度和疾病进展的标志物是血清淀粉样蛋白 A（SAA）的过度表达，其水平在其他疾病中与 SAA 淀粉样变性的风险相关。为了了解 SAA 淀粉样变性是否也是 SARS-CoV-2 感染的长期风险，我们使用长全原子分子动力学模拟来研究 SARS-CoV-2 蛋白片段对 SAA 淀粉样形成的影响。通过 40 μs 的采样，我们发现位于包膜蛋白 C 末端的九残基 SK9 片段的存在通过三种机制增加了 SAA 纤维形成的倾向：它降低了脂质转运六聚体的稳定性，使平衡向单体移动，增加了聚合倾向构象在产生的链中的频率，并提高了 SAA 纤维的稳定性。因此，我们的结果表明，SAA 淀粉样变性和相关病理可能是 SARS-CoV-2 感染的长期风险。
