A large population in the world has been infected by COVID-19. Understanding the mechanisms of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is important for the management and treatment of COVID-19. When it comes to the infection process, one of the most important proteins in SARS-CoV-2 is the spike (S) protein, which is able to bind to human Angiotensin-Converting Enzyme 2 (ACE2) and initializes the entry of the host cell. In this study, we implemented multiscale computational approaches to study the electrostatic features of the interfaces of the SARS-CoV-2 S protein receptor binding domain and ACE2. The simulations and analyses were performed on highperformance computing resources in the Texas Advanced Computing Center. Our study identified key residues on SARS-CoV-2, which can be used as targets for future drug design. The results shed light on future drug design and therapeutic targets for COVID-19. & THE NUMBER OF confirmed cases of Coronavirus Disease 2019 (COVID-19) is increasing dramatically 1 due to the fast spread of SARS-CoV-2. The large coronavirus family includes hundreds of viruses that usually do not pose a threat to human health. SARS-CoV-2 is the seventh member of those coronaviruses that infect the human body. Of these, four (HCoV-229E, HCoV-OC43, HCoV-NL63, HKU1) 2 cause mild to moderate symptoms, while the other three can cause serious, even fatal diseases. SARS coronavirus (SARS-CoV) broke out in 2002 and caused Severe Acute Respiratory Syndrome (SARS). MERS coronavirus (MERS-CoV)
COVID-19 is increasingly affecting human health and global economy. Understanding the fundamental mechanisms of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is highly demanded to develop treatments for COVID-19. SARS-CoV and SARS-CoV-2 share 92.06% identity in their N protein RBDs’ sequences, which results in very similar structures. However, the SARS-CoV-2 is more easily to spread. Utilizing multi-scale computational approaches, this work studied the fundamental mechanisms of the nucleocapsid (N) proteins of SARS-CoV and SARS-CoV-2, including their stabilities and binding strengths with RNAs at different pH values. Electrostatic potential on the surfaces of N proteins show that both the N proteins of SARS-CoV and SARS-CoV-2 have dominantly positive potential to attract RNAs. The binding forces between SARS-CoV N protein and RNAs at different distances are similar to that of SARS-CoV-2, both in directions and magnitudes. The electric filed lines between N proteins and RNAs are also similar for both SARS-CoV and SARS-CoV-2. The folding energy and binding energy dependence on pH revealed that the best environment for N proteins to perform their functions with RNAs is the weak acidic environment.
One quarter of the world’s population are infected by Mycobacterium tuberculosis (Mtb), which is a leading death-causing bacterial pathogen. Recent evidence has demonstrated that two virulence factors, ESAT-6 and CFP-10, play crucial roles in Mtb’s cytosolic translocation. Many efforts have been made to study the ESAT-6 and CFP-10 proteins. Some studies have shown that ESAT-6 has an essential role in rupturing phagosome. However, the mechanisms of how ESAT-6 interacts with the membrane have not yet been fully understood. Recent studies indicate that the ESAT-6 disassociates with CFP-10 upon their interaction with phagosome membrane, forming a membrane-spanning pore. Based on these observations, as well as the available structure of ESAT-6, ESAT-6 is hypothesized to form an oligomer for membrane insertion as well as rupturing. Such an ESAT-6 oligomer may play a significant role in the tuberculosis infection. Therefore, deeper understanding of the oligomerization of ESAT-6 will establish new directions for tuberculosis treatment. However, the structure of the oligomer of ESAT-6 is not known. Here, we proposed a comprehensive approach to model the complex structures of ESAT-6 oligomer inside a membrane. Several computational tools, including MD simulation, symmetrical docking, MM/PBSA, are used to obtain and characterize such a complex structure. Results from our studies lead to a well-supported hypothesis of the ESAT-6 oligomerization as well as the identification of essential residues in stabilizing the ESAT-6 oligomer which provide useful insights for future drug design targeting tuberculosis. The approach in this research can also be used to model and study other cross-membrane complex structures.
Dengue virus causes serious diseases and deaths in the world. Understanding the fundamental mechanisms of dengue virus is highly demanded to develop treatments for dengue virus caused diseases. Here, we present a computational work which focused on the stability of dengue viral capsid. The interactions among E proteins on the dengue viral capsid were studied using several computational approaches. It was found that the electrostatic distribution on a single E protein monomer is highly inhomogeneous, which makes an E protein strongly binding with another E protein. This is the reason why all the E proteins form homodimers as the basic units on the whole dengue viral capsids. The pKa calculations of E proteins demonstrated that the folding energy of an E protein is low and stable in the range of pH 6–10, which is different from many other proteins that are stable at certain pH. The pH dependence of binding energy of E protein homodimer shows that the binding energy is low and independent from pH when the pH is also in the range of 6–10. This finding implies that the dengue virus can survive in a wide range of pH, which can explain why the dengue virus is so widely distributed in the world and spreads fast.
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