Simulations of Lipid Sorting Effects near Transmembrane Peptide Pubblico

Abstract

A biological membrane is a dynamic structure composed of a diverse set of proteins and other biomolecules embedded in a lipid bilayer containing many different types of lipid. The diversity of lipids and proteins raises the question of whether lipids of different types are distributed randomly in the membrane, or associate preferentially with particular proteins. The hydrophobic matching concept, which suggests that peptides are most stable when inserted in bilayers whose hydrophobic thickness matches the peptide's hydrophobic span, is considered one of the most important factors in the lipid-peptide interplay. In bilayers containing lipids with different hydrophobic tail lengths, the hydrophobic matching effect would in general sort lipids resulting in enrichment of the best hydrophobic matched lipid type near peptide. Various experimental methods have been applied to measure this sorting, in model bilayer systems with just a few components, but face many difficulties in interpretation due to the disorder and fluidity of the bilayer. Molecular dynamics (MD) computer simulation methods have been successfully applied to study lipid bilayers with one lipid type, and could usefully complement these experiments. However, this conventional method is not efficient enough to study systems containing more than one lipid type, since slow lipid diffusion rate will require long molecular dynamics simulations, exceeding readily available computational capacities, to adequately sample the distribution states of the lipid mixtures. In this study, a hybrid Monte Carlo-molecular dynamics (MC-MD) approach, which uses mutation moves to interchange lipid types throughout the system within the semi-grand canonical ensemble, is used to overcome the simulation difficulty of lipid diffusion. Pairs of saturated phosphatidylcholine lipids, distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and didecanoylphosphatidylcholine (DDPC), differing by four carbons in the lengths of their acyl tails, are selected to form two-component lipid bilayers. The lipid redistribution in mixed lipid bilayer containing DSPC-DMPC or DMPC-DDPC, induced by an embedded transmembrane peptide is investigated in using MC-MD simulation. Firstly, the alpha helical NeuTM35 peptide is chosen, in which position restraints are applied to the peptide backbone to avoid helix unraveling. Enrichment of DMPC is found in the DMPC-DDPC system. Secondly, study of WALP23/KALP23 peptide from the more stable alpha helical peptide family suggests a strong peptide tilt in the lipid bilayer to accommodate hydrophobic matching instead of changing the bilayer thickness. Thirdly, strong thickness perturbations but weak sorting of lipids is observed in gramicidin A transmembrane ion channel, suggesting hour-glass shape and strong tilt of the peptide would account for reduction of lipid sorting. Finally, a large cylindrical beta barrel OmpA peptide is investigated. Both hydrophobic matching and hydrophobic sorting effects are evident, and the difference in degree of sorting for DMPC-DDPC and DSPC-DMPC systems validates the quadratic relationship of free energy change and hydrophobic mismatch early predicted by theory. The atomistic simulation result also suggests that Coarse Grained model can be used in studying hydrophobic sorting by MD simulations.

Table of Contents

List of Tables...vii
List of Figures...viii
References to Previously Published Work...x
1.Introduction...1

1.1. Background and Overview...1
1.2. Hybrid Molecular Dynamics and Monte-Carlo Methods...12
1.3. Outline of Thesis...13

2. Atomistic Simulation of Hydrophobic Matching Effects on Lipid Distribution Near a Monomer of Neu/Erb2 Transmembrane Domain...17

2.1. Abstract...17
2.2. Introduction...18
2.3. Method...20

2.3.1. Molecular Dynamics and Hybrid MC-MD Setup...20
2.3.2. Configuration Construction...21
2.3.3. Positional Constraint of Peptide in Simulation...22
2.3.4. Equilibration...23
2.3.5. Simulations...24

2.4. Results and Discussion...26
2.5. Conclusions...36

3. Hydrophobic Sorting Effect Studies with Engineered WALP/KALP Alpha Helices...38

3.1. Introduction...38
3.2. Method...39
3.3. Results and Discussion...40
3.4. Conclusions...42

4. Atomistic Simulation of Hydrophobic Sorting Effects Near Beta Helix: the Gramicidin A Transmembrane Ion Channel...43

4.1. Abstract...43
4.2. Introduction...43
4.3. Method...47

4.3.1. Simulation Configuration...47
4.3.2. System Construction...48

4.4. Results and Discussion...50

4.4.1. Hydrophobic Matching...50
4.4.2. Hydrophobic Sorting...54
4.4.3. Peptide Tilt...57

4.5. Conclusions...58

5. Simulations of Lipid Sorting Effects near Beta Barrel Peptide with Atomistic Model and Coarse Grained Model...60

5.1. Abstract...60
5.2. Introduction...60
5.3. Method...64

5.3.1. Coarse-grained model simulations...64
5.3.2. Atomistic model simulations...65
5.3.3. Mixed Monte Carlo/MD simulations...67
5.3.4. Thickness Analysis...67

5.4. Results and Discussion...68

5.4.1. Coarsed Grained System...68
5.4.2. Atomistic System...72

5.5. Conclusions...84

References...86

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Physical
Parola chiave	Hydrophobic Sorting Monte Carlo Simulation Molecular Dynamics Transmembrane Peptide Lipid
Committee Chair / Thesis Advisor	Kindt, James, Emory University
Committee Members	Lutz, Stefan, Emory University Bowman, Joel M, Emory University

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