未经证实:新的SARS-CoV-2变体的迅速传播突出了SARS-CoV-2尖峰受体结合域(RBD)在与人ACE2受体相互作用中发生的突变在感染中发挥的关键作用。在这种情况下,它迫切需要开发新的快速工具,以快速预测ACE2对SARS-CoV-2尖峰RBD蛋白变体的亲和力,以便与临床上正在进行的SARS-CoV-2基因组测序活动一起使用,旨在获得有关新变种的传播性和毒力的线索,以防止新的疫情爆发,并在下午3点的背景下快速估计疾病的严重程度。
未经批准:在我们的研究中,我们使用计算管道来计算SARS-CoV-2尖峰RBD/ACE2蛋白-蛋白界面上的相互作用能,以选择一组表征的关注/感兴趣的感染性变体(VoC/VoI)。通过使用我们的管道,我们为VoCB.1.1.7-UnitedKingdom(携带关注/兴趣N501Y的突变,S494P,E484K在RBD),P.1-日本/巴西(RBD突变:K417T,E484K,N501Y),B.1.351-南非(RBD突变:K417N,E484K,N501Y),B.1.427/B.1.429-加利福尼亚(RBD突变:L452R),B.1.141(RBD突变:N439K),以及最近的B.1.617.1-印度(RBD突变:L452R;E484Q)和B.1.620(RBD突变:S477N;E484K)。然后,我们使用获得的SARS-CoV-2尖峰RBD/ACE2蛋白复合物的3D比较模型来预测蛋白质-蛋白质界面的相互作用能。
UNASSIGNED:沿着SARS-CoV-2突变数据库筛选和突变定位分析,确定VoC/VoI刺突蛋白最危险的突变主要位于SARS-CoV-2刺突“船形”受体结合基序的三个区域,在RBD域上。值得注意的是,P.1日本/巴西变异存在三个突变,K417T,E484K,N501Y,沿着整个受体结合基序定位,这显然决定了SARS-CoV-2尖峰RBD/ACE2蛋白-蛋白界面的最高相互作用能,在那些计算。相反,还观察到,在“船尾”或“弓”区域用碱性残基(E484K或N439K)替换单个酸性/亲水性残基,RBD上的船形受体结合基序,似乎确定与ACE2受体的相互作用能量高于在“船体”区域或其他多个突变体发生的单个突变时观察到的相互作用能量。此外,我们的管道允许搜索ACE2结构相关的蛋白质,即,THOP1和NLN,值得研究它们可能参与与SARS-CoV-2尖峰蛋白的相互作用,在那些显示ACE2低表达的组织中,或作为未来尖峰变体的新型受体。一个免费的网络工具,用于在SARS-CoV-2尖峰RBD/ACE2蛋白质-蛋白质界面上进行相互作用能的计算机计算,从研究的尖峰和/或ACE2变体的序列开始,已通过以下网址向科学界提供:https://www。mitoairm.it/covid19亲和力。
UNASSIGNED:在PPPM/3PM的上下文中,通过所提供的网络服务采用所描述的管道,以及正在进行的SARS-CoV-2基因组测序,将有助于预测未来患者测序的新变异的传播性,取决于SARS-CoV-2基因组测序活性和特定的氨基酸替换和/或其在SARS-CoV-2尖峰RBD上的位置,发挥所有可能的反作用,以防止新爆发的最有害情况,考虑到更大的传播性不一定与疾病的更严重表现有关。
UNASSIGNED:在线版本包含补充材料,可在10.1007/s13167-021-00267-w获得。
UNASSIGNED: The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM.
UNASSIGNED: In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein-protein interface.
UNASSIGNED: Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike \"boat-shaped\" receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the \"stern\" or \"bow\" regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the \"hull\" region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, starting from the sequences of the investigated spike and/or ACE2 variants, was made available for the scientific community at: https://www.mitoairm.it/covid19affinities.
UNASSIGNED: In the context of the PPPM/3PM, the employment of the described pipeline through the provided webservice, together with the ongoing SARS-CoV-2 genomic sequencing, would help to predict the transmissibility of new variants sequenced from future patients, depending on SARS-CoV-2 genomic sequencing activities and on the specific amino acid replacement and/or on its location on the SARS-CoV-2 spike RBD, to put in play all the possible counteractions for preventing the most deleterious scenarios of new outbreaks, taking into consideration that a greater transmissibility has not to be necessarily related to a more severe manifestation of the disease.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13167-021-00267-w.