University of Illinois Urbana-Champaign

Computational investigation of membrane proteins across species and functional classes

Hasdemir, Hale Siir

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

Description

Title
Computational investigation of membrane proteins across species and functional classes
Author(s)
Hasdemir, Hale Siir
Issue Date
2025-11-24
Director of Research (if dissertation) or Advisor (if thesis)
Tajkhorshid, Emad
Doctoral Committee Chair(s)
Tajkhorshid, Emad
Committee Member(s)
  • Das, Aditi
  • Shukla, Diwakar
  • Pogorelov, Taras
Department of Study
School of Molecular & Cell Bio
Discipline
Biophysics & Quant Biology
Degree Granting Institution
University of Illinois Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • 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
Abstract
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.
Graduation Semester
2025-12
Type of Resource
Thesis
Handle URL
https://hdl.handle.net/2142/132648
Copyright and License Information
Copyright 2025 Hale Siir Hasdemir

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Graduate Theses and Dissertations at Illinois