School of Physics Thesis Dissertation Defense

Presenter:          Zijian Zhang

Title:                    PROTEIN EVOLUTION IN THE MEMBRANE OF MICROSCOPIC ORGANISMS: INSIGHTS FROM GRAM-NEGATIVE BACTERIA AND SARS-COV-2 THROUGH MODELING AND MACHINE LEARNING

Date:                   Thursday, August 17, 2023

Time:                   1:30 p.m.

Location:            Boggs Viz-Lab

Via Zoom:          https://gatech.zoom.us/j/91023596959

Committee members:

Dr. James (JC) Gumbart, School of Physics, Georgia Institute of Technology (advisor)

Dr. Simon Sponberg, School of Physics, Georgia Institute of Technology

Dr. Peter Yunker, School of Physics, Georgia Institute of Technology

Dr. Ingeborg Schmidt-Krey, School of Chemistry & Biochemistry, Georgia Institute of Technology

Dr. Lynn Kamerlin, School of Chemistry & Biochemistry, Georgia Institute of Technology

Abstract: “This dissertation explores the evolution and development of proteins, specifically membrane-embedded proteins in microorganisms, including viruses and bacteria, using computational methodologies like Molecular Dynamics (MD) simulations and machine learning techniques.

We first study outer-membrane proteins (OMPs) in Gram-negative bacteria, specifically the Escherichia coli protein OmpX. Through simulation of its engineered variants, we find a link between β-barrel size, shape, and the presence of inward-facing glycines. we find that the fraction of glycines in β-barrels decreases as the strand number increases, suggesting an evolutionary role in the addition or removal of glycine in OMP sequences.

Next, our investigation shifts to the Spike protein in SARS-CoV and SARS-CoV-2 viruses. Despite differences in their receptor-binding domains, the two proteins bind to the human ACE2 receptor in similar ways. Using MD simulations, machine learning, and free-energy perturbation calculations, we quantify these subtle mutations and demonstrate how evolutionary changes directly influence binding affinity.

Lastly, we study the glycosylation profiles of virus variants and their impact on the glycan shield of the Spike protein. Our findings reveal that the Spike protein in the Omicron variant is less enveloped by glycans, affecting the accessible area in specific residues.

This work sheds light on the evolution of membrane proteins, their structure, interactions, and glycan shields, offering valuable insights into protein evolution.”