PDF(Pubmed)
Abstract：
The SARS-CoV-2 claimed millions of lives, globally. Occurring from Wuhan (wild type) in December, 2019, it constantly mutated to Omicron (B.1.1.529), the predecessor to Delta. Omicron having ~ 32 spike mutations has variable infectivity-multiplicity-immuno-invasive properties. Understanding of its mutational effect on ACE2-binding/disease severity and developing preventive/therapeutic strategies are important. The binding affinities of Wuhan/Delta/Omicron spikes (PDB/GISAID/SWISS-MODEL) were docked (HADDOCK2.4) with ACE2 and compared by competitive-docking (PRODIGY). The protein structural stability was verified by kinetic-data/Ramachandran-plot (Zlab/UMassMedBioinfo). After several trials, a 59 amino acid (453ARG-510VAL) peptide-cut (Expasy-server) of the wild-type spike RBD with some desired mutants (THR500SER/THR500GLY/THR500ALA/THR500CYS) was blindly/competitively docked (PyMOL-V2.2.2) to block the Omicron-ACE2 binding. We examined molecular dynamic simulation (iMOD-server, with 9000 cycles/300 k-heating/1 atm pressure for system equilibration for 50 ns-run) of ACE2 and two CUTs with different SARS-CoV-2 variants. The binding-affinity of Omicron-ACE2 is slightly higher than the rest two in competitive docking setup. During individual (1:1) docking, Omicron showed little higher than wild type but much weaker binding affinity than Delta. Competitive docking suggests ten H-bonding (1.3-2.4 Å) with highly favorable energy values/Van-der-Walls-force/Haddock score for more stable-binding of Omicron-RBD with ACE2. Blind docking of different CUTs (wild/mutants) and Omicron to ACE2 completely rejected the Omicron-RBD from ACE2-target. The best blocking/binding affinity of -16.4 and -13 kcal/mole were observed in the case of THR500SER and THR500GLY, respectively, with multiple H-bonding 1.9-2.2 Å. These are supported by the MD-simulation results. So, the spike binding affinities were Delta > Omicron > wild in 1:1 docking with ACE2. Considering the wild type is non-existing nowadays, Omicron showed less ACE2 binding properties. The 59 cut of spike-RBD and its mutant THR500SER/THR500GLY may be further screened as universal blockers of this virus.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s11224-022-02022-x.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s11224-022-02022-x.
摘要：
SARS-CoV-2夺去了数百万人的生命,全球。12月在武汉发生（野生型），2019年，它不断突变为Omicron（B.1.1.329），三角洲的前身。具有约32个尖峰突变的Omicron具有可变的感染性-多重性-免疫侵入性。了解其对ACE2结合/疾病严重程度的突变作用以及制定预防/治疗策略非常重要。将武汉/Delta/Omicron尖峰（PDB/GISAID/SWISS-MODEL）的结合亲和力与ACE2对接（HADDOCK2.4），并通过竞争对接（PRODIGY）进行比较。通过动力学数据/Ramachandran图(Zlab/UMassMedBioinfo)验证蛋白质结构稳定性。经过几次试验,具有一些所需突变体（THR500SER/THR500GLY/THR500ALA/THR500CYS）的野生型刺突RBD的59个氨基酸（453ARG-510VAL）肽切割（Expasy-server）盲目/竞争性对接（PyMOL-V2.2.2）以阻断Omicron-ACE2结合。我们检查了分子动态模拟(iMOD服务器，具有9000次循环/300k加热/1atm压力，用于系统平衡50ns运行）的ACE2和两个具有不同SARS-CoV-2变体的CUT。在竞争性对接设置中，Omicron-ACE2的结合亲和力略高于其余两个。在个人(1:1)对接期间，Omicron显示出略高于野生型，但比Delta弱得多的结合亲和力。竞争性对接建议十个H键（1.3-2.4µ），具有非常有利的能量值/Van-der-Walls-force/Haddock评分，可使Omicron-RBD与ACE2更稳定地结合。不同CUT（野生型/突变体）和Omicron与ACE2的盲对接完全拒绝了ACE2靶标的Omicron-RBD。在THR500SER和THR500GLY的情况下，观察到-16.4和-13千卡/摩尔的最佳阻断/结合亲和力，分别,具有多个H键1.9-2.2µ。MD模拟结果支持这些。所以,在与ACE2的1：1对接中，刺突结合亲和力为Delta>Omicron>wild。考虑到野生型现在不存在，Omicron显示较少的ACE2结合性质。可以进一步筛选spike-RBD及其突变体THR500SER/THR500GLY的59个切口作为该病毒的通用阻断剂。
■在线版本包含补充材料，可在10.1007/s11224-022-02022-x获得。
■在线版本包含补充材料，可在10.1007/s11224-022-02022-x获得。
