Role of lipid-protein interactions in modulating the membrane protein function

Biological membranes are recognized as cell armors, protecting them from surrounding, nevertheless at the same time hosting some of the most important cellular processes. Biological membranes are complex assemblies consisting of diverse lipids. They house a broad range of proteins, known as membrane proteins, the functionality of which can be directly modulated by the lipid environment. Membrane proteins mediate different cellular processes that are fundamental for the flourishing of biological cells, such as translocation of ions and other solutes across membrane, signal transduction, and cell-cell recognition/communication. Despite tremendous biophysical/biochemical advances in understanding the detailed structures and functional states of different proteins, the complexity of membrane proteins demands a higher level of investment to decipher their critical roles in cellular processes. Molecular dynamics (MD) simulations have proven to be a powerful technique in shedding light on the dynamics of macromolecular structures and providing an atomic-resolution picture for diverse biological systems, including membrane proteins. The exquisite details/information provided by MD in conjunction with various experimental techniques, e.g., cryo-EM microscopy, X-ray crystallography, NMR, and electrophysiology, can assist us to better tackle complicated biological problems. Here, I have employed MD simulations and advance sampling techniques to study three membrane proteins with the focus of their detailed interactions with lipid molecules: (1) Prestin, a motor protein which functions as the sound amplifier in outer hair cells (OHCs); (2) P-glycoprotien (Pgp), an ATP-binding cassette (ABC) transporter known to cause multi-drug resistance (MDR) in cancer cells, (3) HnSpns, the bacterial homolog of Spns2 known to modulate sphingosine-1-phosphate (S1P) signaling. Exploiting MD simulation in understanding the role of lipids in modulating the functionality of these membrane proteins requires statistically-valid results which only can be achieved if the simulations are replicated. To address this issue, I was involved in the development of a software, known as Membrane Mixer Plugin (MMP), which employs non-equilibrium MD simulations to quickly shuffle lipid molecules in MD generated systems, and therefore, construct membrane/membrane-protein complexes with the same lipid compositions and different lipid configurations. The generated complexes from MMP can be simulated independently, increasing the amount of sampling.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics & Quant Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Dehghanighahnaviyeh, Sepehr

Contributors dc:contributor

• Tajkhorshid, Emad
• Shukla, Diwakar
• Aksimentiev, Alek
• Procko, Eric

• membrane proteins
• molecular dynamics simulations
• lipid-protein interactions

Statement dc:rights

• Copyright 2022 Sepehr Dehghanighahnaviyeh

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/117622

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F117622