Alfie-Louise Brownless, QBioS Thesis Proposal

Quantitative Biosciences Thesis Proposal
Alfie-Louise Brownless
School of Chemistry and Biochemistry

Harnessing Biomolecular Simulations to Understand Enzyme Selectivity and Allosteric Regulation 
Tuesday, June 25, 2024, at 2:00 pm
In Person Location: EBB 4029
Zoom Link: https://gatech.zoom.us/j/92992806244?pwd=cE1hYVY2TFZwRkhCWjl3S2pDZTd5UT09 
Meeting ID: 929 9280 6244
Passcode: 322647
Open to the Community

Advisor: 
Dr. S.C. Lynn Kamerlin (School of Chemistry and Biochemistry)

Committee Members:
Dr. Sam Brown (School of Biological Sciences) 
Dr. JC Gumbart (School of Physics)
Dr. Christine Heitsch (School of Mathematics)
Dr. Mikael Elias (School of Biological Sciences – University of Minnesota)

Abstract:
Biological systems are driven by interactions across fundamental catalytic microscopic complexes, notably proteins and nucleic acids. Despite the crucial importance of these complexes, their small scale makes the comprehensive study of their dynamics and function nearly impossible by experiment alone. As a result, we seek to better understand two classes of enzymes via computational simulation methods. We propose to utilize biophysical simulations, including classical molecular dynamics (MD) simulations, enhanced sampling metadynamics approaches, and empirical valence bond (EVB) calculations, in order to characterize protein dynamics, determine reaction mechanisms, and quantify reaction barriers.

This thesis proposal is divided into two components. First, we propose an exploration of the MacQ and PvdQ acylases, enzymes which are known to exhibit bacterial quorum-quenching ability with varying substrate affinity. Utilizing classical MD, we will determine structural factors which facilitate MacQ’s broader substrate specificity. We will then use structural information to engineer altered enzymes with even greater substrate promiscuity. We will use EVB methods along with experimental collaborations to test the catalytic prowess of our engineered enzymes. Results will provide an avenue for producing efficient quorum-quenching enzymes, leading to both industrial and health benefits.

During our second phase, we will investigate the SHP-1 and SHP-2 protein tyrosine phosphatases (PTPs), which are known to play important roles in various oncogenic pathways. We will use both classical MD and enhanced sampling metadynamics techniques in order to thoroughly characterize active site loop movement in SHP-1/2 and compare to other more well-studied members of the PTP family. We will further determine the effects of known oncogenic mutations on SHP-1 and SHP-2 protein dynamics and catalysis to propose methods for altering these proteins for the application of cancer therapeutics.