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Transition from the Down State to the Up State of RBD Protein in SARS -CoV- 2

Taeb, Hoda | 2021

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 54559 (04)
  4. University: Sharif University of Technology
  5. Department: Physics
  6. Advisor(s): Ejtehadi, Mohammad Reza; Ghasemi Tarei, Maryam
  7. Abstract:
  8. Since the first observed case in December 2019, millions of people have been infected by Coronavirus disease 2019 (COVID-¬19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS¬-CoV-¬2). Located on the viral membrane, trimeric spike glycoprotein is one of the most crucial parts of the virus’ structure as it is responsible for the attachment and entry of the virus to host cells. The spike glycoprotein undergoes hinge-like conformational movements and its receptor¬binding domains (RBD) can be in either an accessible (up) state or an inaccessible (down) state to the host cell receptors, such as ACE2. Having performed Molecular Dynamics Simulations and Targeted Molecular Dynamics (TMD), here in this work, we have investigated important properties of the down and up states and the transition between them, respectively. Moreover, we oxidized 2 amino acids located in the vicinity of RBD and assessed the effects of such oxidation on the mobility of RBD and its transition from the down to the up state. In Targeted Molecular Dynamics (TMD), external forces are applied to spike’s atoms by defining virtual springs. This helps to overcome the potential barrier existing between the two stable states of the spike protein and simulate the conformational transition between these two states in the time scale of the molecular dynamics simulation. Moreover, by calculating the difference of work which is done during the conformational transitions in the native and oxidized proteins, we can have an estimation of deviation in free energy differences between these two proteins. What we have found is that the RBD has less mobility in its down state, whether it is oxidized or native. This might happen due to some hydrogen bonds and salt bridges existing between the RBD and other parts of the spike protein, especially one of the three monomers, since during the transition some of those bonds break. In addition, we have found out that glycans such as N165B, N343B, and N343A play an important role in the establishment of hydrogen bonds. We have also shown that the oxidation not only makes the transition smoother and slower, but under oxidation more work is needed (around 608 kJ/mol compared to native). This could result in the harder transition and as the transition gets harder, the probability by which the virus connects to host cells would decline consequently
  9. Keywords:
  10. Biophysics ; Soft Matter Physics ; Oxidation ; Molecular Dynamic Simulation ; Condensed Matter ; Cold Atmospheric Plasma ; Spike Protein ; Targeted Molecular Dynamics (TMD) ; COVID-19 ; SARS-CoV-2 Virus

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