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Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection.
Journal of General Virology ( IF 3.8 ) Pub Date : 2020-09-01 , DOI: 10.1099/jgv.0.001452
Jingfang Wang 1 , Xintian Xu 1, 2 , Xinbo Zhou 3 , Ping Chen 4, 5 , Huiying Liang 4 , Xuan Li 5 , Wu Zhong 3 , Pei Hao 1, 2, 4
Affiliation  

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol−1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

中文翻译:

SARS-CoV-2穗蛋白与穿山甲ACE2或人ACE2自然变异体结合的分子模拟显示了易感性的改变。

我们构建了SARS-CoV-2穗蛋白与穿山甲或病毒传播受体人类ACE2结合的复杂模型,并使用分子动力学模拟估算了结合自由能的变化。SARS-CoV-2可以与穿山甲和人ACE2结合,但由于结合自由能增加(9.5 kcal mol -1,对穿山甲ACE2的结合亲和力明显较低))。人类ACE2是最多态的基因之一,我们从dbSNP数据库中鉴定出317个错义单核苷酸变异(SNV)。三种SNV,即E329G(rs143936283),M82I(rs267606406)和K26R(rs4646116),其结合自由能显着降低,这表明与野生型ACE2相比,结合亲和力更高,并且对SARS-CoV-2感染的易感性更高。他们。其他三个SNV D355N(rs961360700),E37K(rs146676783)和I21T(rs1244687367)的结合自由能显着增加,这表明结合亲和力降低,对SARS-CoV-2感染的敏感性降低。
更新日期:2020-09-29
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