Document Type



Doctor of Philosophy (PhD)



First Advisor's Name

Prem P. Chapagain

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Bernard S. Gerstman

Second Advisor's Committee Title

Co-committee chair

Third Advisor's Name

Jorge L. Rodriguez

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Yuan Liu

Fourth Advisor's Committee Title

Committee member


Physics, Biophysics, Molecular Dynamics Simulation, SARS-CoV-2, Omicron, Multidrug transporters, PfMATE, envelope protein, drug resistance, conformational changes of protein

Date of Defense



Proteins do versatile work in cells. They require a cascade of structural changes to perform different tasks like binding to the other neighboring biomolecules, transporting small chemicals, activating a chemical reaction, etc. The structural conformations of proteins can be critical in changing their working ability. In this dissertation, I investigated the role of conformational changes of viral protein, e.g., spike and envelope protein of SARS-CoV-2, and bacterial protein, e.g., multidrug transporter and toxic extrusion protein- PfMATE from Pyrococcus furiosus. Also, I performed molecular docking-based drug screening targeting the E protein to suggest a set of drugs that can be repurposed after cautious clinical trials.

Recently, the Omicron variant of SARS-CoV-2 popped up with the highest number of mutations and showed unparallel transmissibility compared to other strains of the virus. I computationally investigated the role of the Omicron RBD mutations on its structure and interactions with surrounding domains in the spike trimer and ACE2. My results suggest that, compared to the WT and Delta, the mutations in the Omicron RBD facilitate a more efficient RBD “down” to “up” conformation and ACE2 attachment. These effects, combined with antibody evasion, may have contributed to its dominance over Delta.

In the PfMATE project, I performed molecular dynamics (MD) simulations to investigate the flexibility of the five different PfMATE structures. Subtle analyses based on MD provide information on how protonation or Na+ can induce cascading structural changes responsible for the transition between the IF and OF configurations.

The E protein of SARS-CoV-2 plays an essential role in assembling the virus, mediating the budding process, and releasing the progeny viruses into the host cells. I took 3800 US Food and Drug Administration (FDA) approved and investigational drugs and targeted the E protein to obtain the drug-protein complexes using molecular docking. The top 6 complexes were selected based on the docking score and embedded in the ERGIC membrane to relax with unconstrained MD simulation to investigate their stability. Their pharmacological properties were also predicted. The top-scoring, most stably bound, and clinically safe compounds are proposed as potential candidates for drug repurposing.







Rights Statement

Rights Statement

In Copyright. URI:
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).