Modeling and characterizing heterogeneous biological membranes and their permeability to gas

Shinn, Eric J.

Permalink

https://hdl.handle.net/2142/127382 Copy

Description

Title

Modeling and characterizing heterogeneous biological membranes and their permeability to gas

Author(s)

Shinn, Eric J.

Issue Date

2024-12-06

Director of Research (if dissertation) or Advisor (if thesis)

Tajkhorshid, Emad

Doctoral Committee Chair(s)

Tajkhorshid, Emad

Committee Member(s)

• Grosman, Claudio
• Aksimentiev, Alek
• Gruebele, Martin

Department of Study

School of Molecular & Cell Bio

Discipline

Biophysics & Quant Biology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• MD simulations
• membranes
• permeability

Abstract

Molecular dynamics (MD) is a computational tool that makes use of powerful computing capabilities, applying the fundamental laws of physics to numerically solve the motion of a system of particles in fine detail. Guided by experimental data, such a technique can be applied to study biological systems like the cell membrane. In the context of my PhD research under the guidance of Professor Emad Tajkhorshid, MD was applied to study biological membrane systems, largely their permeability to the metabolic gases O2 and CO2. Membranes are an indispensable component of life at the cellular level, functioning as a selective, semipermeable barrier. They distinguish a cell from its environment and endow cells with the capacity to exist in homeostatic equilibrium by providing a regulatory system for the transmembrane flow of metabolites. As such, a fundamental understanding of membranes is key to understanding life. Over the course of my studies, I became intellectually involved with the study of membrane at multiple levels---the pure lipid phase, protein-lipid membranes, and large membrane assemblies---which is summarized in this thesis. For the purpose of studying membrane permeability, I identified a need for a method capable of generating and sustaining concentration gradients in MD simulations that utilize periodic boundary conditions. I implemented such a method so that a net flux of a permeant across a membrane could be observed in simulation, and whose measurement could be used to characterize the permeability of a membrane. Sustained gradients were generated by unidirectionally biasing the motion of permeant molecules to move across the periodic boundary using Grid-steered MD, a non-equilibrium simulation technique. A validation study of the concentration gradient method was conducted for a pure lipid membrane system, which found the method to be a suitable means of generating the gradient condition and characterizing membrane permeability. Next, the role of proteins in the facilitation of gas transport across the membrane was investigated in collaboration with experimental colleagues. Examining AQP5, the integral membrane protein was thoroughly examined by various means. The central and monomeric pores of the protein were characterized by measurements of their pore radius and hydration status. The free energy of partitioning for various gases in the pores was calculated for using implicit ligand sampling. Simulations with the explicit inclusion of CO2 molecules were also conducted to observe their interaction with the protein, which validated the implicit free energy calculations. Concentration gradient simulations were also conducted in which a net flow of CO2 was observed through AQP5, providing convincing evidence that gas can indeed permeate through AQP5, primarily through its central pore. Detailed in the last chapter, work was done on the development of a protocol capable of robustly assembling large, cell-scale membrane systems. Challenges associated with the integration of a large number of protein and lipid molecules into closed membrane compartments were addressed by the methods of the protocol, aiming to do so with the goals of automation and scalability. Assembly of the membrane systems is achieved by first constructing a spherical, lipid shell using a Fibonacci sphere. Meanwhile, an arrangement of the constituent proteins is made by a rapid MD simulation of ultra-coarse grained representations of the proteins. The protein and lipid components are then integrated by etching spaces into the lipid shell to accommodate the proteins. The assembly protocol was utilized to construct a set of large membrane systems, which included protocells, and the envelopes of the Zika virus and SARS-CoV-2. Simulations of the large membrane systems were performed to examine the numerical stability of their construction. Scientific work for the study of biological membranes was performed across a range of spatial scale and complexity, beginning with simple pure lipid bilayer in the study of permeability. By inquiring into the process of permeation across the membrane, considerations have been made on origins of biological function and order, up from their molecular origins to the cellular scale. The work represented by the projects of my PhD studies has culminated in an appreciation for the scales across which biological systems span.

Graduation Semester

2024-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/127382

Copyright and License Information

2024 by Eric J. Shinn. All rights reserved.

Owning Collections