New coronavirus (SARS-CoV-2) _spanspan14span span11 (SARS-CoV-2) receptor_spanspanspan14span_span11 (such as ACE2) causes the S1 and S2 domains in the spike to separate, triggers the conformational change of the S2 domain, and finally leads to the fusion of the virus with the host cell membrane to complete the virus invasion. However, the current structural biology study found that when the new coronavirus spike binds to the ACE2 receptor, only the RBD domain has major conformational changes, and only minor changes occur in other parts, which are not enough to trigger the tightly bound S1 and S2 domains. Separate. Therefore, how the new coronavirus spike binds to the host receptor to trigger the separation of its S1 and S2 domains, which in turn stimulates the S2 membrane fusion protein machinery, is one of the unsolved important issues in the field of coronavirus invasion.
Recently, the international authority of the professional journals Cell Research published online entitled " Mechanical activation of spike fosters SARS-CoV-2 viral infection ” Research paper [1] ,The researchers calculated by biomechanics theory and found that during the invasion of the new coronavirus, a single spike/ACE2 molecule pair at the edge of the virus is subjected to a biological pull of 10-30 skin cattle (1 skin cattle = 10-12 Newtons); binding molecules Dynamic simulation, single-molecule force spectroscopy technology and pseudovirus infection experiment proved for the first time that biological force can enhance the spike/ACE2 interaction and accelerate the separation of S1 and S2 domains, thereby facilitating virus invasion of host cells.
. SARS-CoV-2 RBD (door knocker) interacts with ACE2 (hand), biological force (the child's hand is in a stretched state) regulates the interaction between RBD and ACE2 protein, and promotes the conformational change of the spike protein (the door plug is about to rupture ). Once the door plug is broken (the conformational change of the spike protein is completed), the beast (viral RNA) outside the door will enter (the new coronavirus fuses with the host cell, and the viral RNA genetic material enters the host cell).
This paper reveals the important role of biological pull in the process of new coronavirus particles invading the host through the spike/ACE2 interaction . The biological pulling energy generated during the virus invasion is mainly derived from part of the free energy released by the spike/ACE2 interaction.This energy is further converted into elastic potential energy of the cell-virus system. It mainly consists of two parts: 1. A part of the bending energy is stored in the cell membrane. The relatively soft cell membrane adapts to the morphology of the harder virus particles and is wrapped on the surface for storage; 2. In order to ensure the close attachment of the virus to the cell membrane, the cell -There is biological tension in the spike/ACE2 molecular bond at the edge of the virus contact surface, which stores part of the tensile elastic potential energy. The single-molecule force spectroscopy experiment further proves that the new crown spike/ACE2 interaction is significantly enhanced under the action of cow-level tension. Molecular dynamics simulations show that the pulling force will cause the RBD of the ACE2 binding domain of the new coronavirus spike to rotate, enhance the binding of the spike/ACE2 bond, delay their dissociation, and enhance the attachment of virus particles to the surface of cells expressing ACE2. Moreover, this mechanically enhanced spike/ACE2 interaction effect is more significant on the new coronavirus spike than on the SARS virus spike, providing a new molecular mechanism explanation for the new coronavirus's stronger infectivity than SARS virus .
What’s more interesting is that biological pulling force can accelerate the separation of S1 and S2 domains thousands of times. (Figure 2) 11 . The researchers also accidentally discovered the D614G mutation on the spike of the highly infectious new coronavirus mutant strain (this mutation is a mutation shared by alpha, beta, delta, gamma and lambda strains) can further enhance the binding of spike and ACE2 by 3 times, and accelerate the separation rate of S1 and S2 domains by 35 times. This discovery provides a new molecular mechanism to explain the high infectivity of D614G-related highly pathogenic strains.
The structure of Spike protein and Spike domain of the new corona spike protein induced by the new coronavirus and the biological separation of the spike protein of the new coronavirus model. Kinetic simulation.
In addition, the study also identified a non-RBD blocker that has good neutralization ability and combines both S1 and S2 domains from patients recovered from COVID-19 . The cloned antibody, the antibody can inhibit the rapid dissociation of the S1 and S2 domains by 105 times (Figure 3) . Based on the above findings, researchers have proposed a new antibody screening and design strategy based on locking the S1 and S2 domains of the spike protein to neutralize the coronavirus. The potential is the current new highly pathogenic coronavirus. Mutant strains provide a new and effective blocking strategy.
Figure 3. The model that neutralizes the new coronavirus by locking the separation of the S1 and S2 domains
2pstrong p2p11 Another successful case of cooperation,It is an important breakthrough in biomechanics, mechanobiology, and single-molecule biophysics. It is also a collaboration between Chen Wei and Lou Jizhong’s research group in Cell Research in 2020 to discover the new crown packaging mechanism [2] and another important discovery in the field of viruses . The co-first authors of this research work include Postdoctoral fellow of Zhejiang University School of Basic Medical Sciences Hu Wei Zhang Yong _strong45 strong Ph.D., School of Mechanical Engineering, Zhejiang University PhD student Fei Panyu (medical-industrial cross-section) , Zhejiang University School of Basic Medicine/Hangzhou First People's Hospital Postdoctoral Zhang Tongtong _strong45, Zhejiang Span School of Basic Medicine 11span Postdoctoral fellow Yao Danmei . Zhejiang University School of Basic Medicine/Second Affiliated Hospital Chen Wei Professor, cooperating unit Lou Jizhong researcher, Shanghai University14 and Mechanics Institute of Applied Mathematics and Mechanics Li Zhenhai and New York University Wang Jun are the co-corresponding authors.This work was also supported by West Lake University Zhou Qiang Professor, Xie Qi Professor 11span strong and span _strong from Shandong University .
