Utilizing Computational Methods to Study the Biomolecules

Wenhan Guo, University of Texas at El Paso


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. Kinesins are microtubule-based motor proteins that play important roles ranging from intracellular transport to cell division. Human kinesin-5/Eg5 is essential for mitotic spindle assembly during cell division. By combining molecular dynamics (MD) simulations with other multi-scale computational approaches, we systematically studied the interaction between Eg5 and the microtubule. Our results showed that electrostatic potential on the binding interface of the Eg5 motor domain is dominantly positive while electrostatic potential on the binding interface of αβ-tubulin heterodimer is dominantly negative. Detailed electrostatic distributions on the binding interfaces were illustrated in this work. We found that binding forces between the Eg5 motor domains and the αβ-tubulin heterodimer at different distances are consistent with the attractive electrostatic forces in both directions and magnitudes. Electric field lines between Eg5 and the αβ-tubulin heterodimer indicate a strong, attractive force between Eg5 and the αβ-tubulin heterodimer. The folding and binding energy dependence on pH reveals that the Eg5 motor domain performs its functions best with microtubules in the weak acidic environment. The analyses on hydrogen bonds and salt bridges demonstrate that on the binding interfaces of Eg5 and tubulin heterodimer, the salt bridge plays the most significant role in holding the complex structure. The salt bridge residues on the binding interface of Eg5 are mostly positive, while salt bridge residues on the binding interface of tubulin heterodimer are mostly negative. Such salt bridge residue distribution is consistent with the electrostatic potential calculations. On the contrast, the interfaces between α- and β-tubulins are dominated by hydrogen bonds rather than salt bridges. Compared with the salt bridges between Eg5 and α-tubulin interfaces, the salt bridges between Eg5 and β-tubulin have a greater number and higher occupancies. This asymmetric salt bridge distribution may play a significant role in Eg5’s directionality. The residues involved in hydrogen bonds and salt bridges are identified in this work, which may be helpful for anticancer drug design.

Subject Area

Computational physics|Biophysics

Recommended Citation

Guo, Wenhan, "Utilizing Computational Methods to Study the Biomolecules" (2022). ETD Collection for University of Texas, El Paso. AAI29256979.