Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.
J Biol Chem. 2020 Aug 14;295(33):11742-11753. doi: 10.1074/jbc.RA120.014873. Epub 2020 Jun 25.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的大流行挑战了实验室发现病毒组成和研究健康结果的速度。冠状病毒的小约 30kb ssRNA 基因组使它们能够在物种间传播，同时使人们能够充分了解病毒基因组编码的所有蛋白质。我们采用了蛋白质建模、分子动力学模拟、进化映射和 3D 打印技术，对 SARS-CoV-2 进行了全蛋白质组和动态组学水平的研究。我们建立了病毒综合结构进化动态数据库（RRID:SCR_018793 中的 VIStEDD），以促进未来的发现和教育用途。在这里，我们重点介绍了 VIStEDD 在 nsp6、核衣壳 (N) 和刺突 (S) 表面糖蛋白方面的应用。对于 nsp6 和 N，我们发现了高度保守的表面氨基酸，这些氨基酸可能驱动蛋白质-蛋白质相互作用。在表征病毒 S 蛋白时，我们开发了一种定量动力学互相关矩阵，以深入了解其与血管紧张素 I 转换酶 2 (ACE2)-溶质载体家族 6 成员 19 (SLC6A19) 二聚体的相互作用。使用这种定量矩阵，我们从 ACE2/SLC6A19/跨膜丝氨酸蛋白酶 2 (TMPRSS2) 的基因组数据库中鉴定出 47 个潜在的功能错义变体，这些变体值得在 SARS-CoV-2 患者中进行基因组富集分析。这些变体存在于 ACE2 半合子男性中，但其出现的频率非常低。存在于约 9%非裔个体中的 ACE2 两个非编码变体(rs4646118 和 rs143185769) 可能调节 ACE2 的表达，并可能与非裔美国人对 SARS-CoV-2 的易感性增加有关。我们提出，这个 SARS-CoV-2 数据库可以帮助研究正在进行的大流行。
