Computational investigation of membrane proteins across species and functional classes

Membrane proteins play central roles in cellular communication, metabolism, and homeostasis, yet experimental characterization of their dynamic interactions with membranes remains highly challenging. In this dissertation, I implement advanced molecular dynamics (MD) simulation workflows to investigate the conformational dynamics, substrate recognition, and lipid-mediated regulatory mechanisms of a diverse set of membrane-associated proteins across species and functional classes, spanning both peripheral and integral membrane proteins. I characterize the membrane-binding mechanism of human beta-2-glycoprotein I, revealing key electrostatic and hydrophobic interactions that drive anionic lipid recognition and identifying a previously unreported lipid-interaction site within its membrane-binding domain. I then explore substrate binding in human cytochrome P450 2J2 using molecular docking, MD simulations, and free energy perturbation calculations, elucidating structural determinants governing regioselective cannabinoid metabolism. Next, I examine lipid-dependent stabilization of the ATP-binding cassette transporter BmrCD from Bacillus subtilis, showing how specific membrane interactions contribute to efflux function and multidrug resistance mechanisms in Gram-positive bacteria. Finally, I investigate LetAB from Escherichia coli, a recently identified lipid transporter that spans the bacterial cell envelope, using atomistic simulations to define a putative phospholipid translocation pathway and establish the functional role of LetA in intermembrane lipid trafficking. Together, these studies demonstrate how computational biophysics can overcome long-standing barriers in membrane protein research by enabling atomic-scale resolution of lipid–protein coupling, rare conformational transitions, and catalytic processes inaccessible to experiment alone, ultimately advancing our understanding of membrane-associated protein function and informing therapeutic and antimicrobial strategies targeting these essential systems.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics & Quant Biology

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Hasdemir, Hale Siir

Contributors dc:contributor

• Tajkhorshid, Emad
• Das, Aditi
• Shukla, Diwakar
• Pogorelov, Taras

• Membrane
• Membrane protein
• Molecular dynamics
• Lipid–protein interactions
• Peripheral membrane protein
• Integral membrane protein
• Beta-2-glycoprotein I
• Antiphospholipid syndrome
• Cytochrome P450
• Cannabinoid metabolism
• Free energy perturbation
• ABC transporter
• BmrCD
• Multidrug resistance
• LetAB
• Lipid transport
• Phospholipid translocation
• Computational biophysics

Statement dc:rights

• Copyright 2025 Hale Siir Hasdemir

Language dc:language

en

Handle dc:identifier

https://hdl.handle.net/2142/132648

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132648