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«COMPUTATIONAL STUDIES OF LIPID OXIDATION AND SIGNALING by Dariush Mohammadyani B.S. in Materials Science, Amirkabir University of Technology, Tehran, ...»

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COMPUTATIONAL STUDIES OF LIPID OXIDATION AND SIGNALING

by

Dariush Mohammadyani

B.S. in Materials Science, Amirkabir University of Technology, Tehran, Iran, 2005

M.S. in Materials Science, University of Tehran, Tehran, Iran, 2008

M.S. in Bioengineering, University of Pittsburgh, Pittsburgh, USA, 2014

Submitted to the Graduate Faculty of

Swanson School of Engineering in partial fulfillment

of the requirements for the degree of

Doctor of Philosophy in Bioengineering University of Pittsburgh

UNIVERSITY OF PITTSBURGH

SWANSON SCHOOL OF ENGINEERING

This dissertation was presented by Dariush Mohammadyani It was defended on February 18th, 2016 and approved by Ivet Bahar, Ph.D., Professor, Department of Computational and System Biology Hulya Bayir, Ph.D., Professor, Department of Critical Care Medicine Bruce Pitt, Ph.D., Professor, Department of Environmental and Occupational Health Partha Roy, Ph.D., Associate Professor, Departmental of Bioengineering Patrick van der Wel, Ph.D., Assistant Professor, Department of Structural Biology Dissertation Advisors: Valerian E. Kagan, Ph.D., Professor, Department of Environmental and Occupational Health Judith Klein-Seetharaman, Ph.D., Professor, Division of Metabolic and Vascular Health, University of Warwick ii Copyright © by Dariush Mohammadyani iii

COMPUTATIONAL STUDIES OF LIPID OXIDATION AND SIGNALING

Dariush Mohammadyani, Ph.D.

University of Pittsburgh, 2016 Introduction: Lipid signaling refers to events involving lipid messengers that bind proteins, which in turn mediate the effects of these lipids on specific cellular responses. The identification of lipid messengers and mechanisms of their interactions with the target proteins are the main pillars of understanding lipid signaling. Lipids function as signals in two ways: (i) chemical modifications of lipids, and (ii) asymmetric distribution of lipids.

Methodology: We utilized computational approaches, including molecular docking, molecular dynamics simulations and bioinformatics, to explore the mechanism of lipid signaling in several cellular pathways.

Oxygenated (ox-)lipid signaling in anti-cancer immunity: Oxygenation is the major metabolic modification generating numerous new molecular species of lipids, which can be involved in signaling processes. The structural role of ox-lipids in lipid droplets (LDs) present in tumor environments was examined. The presence of polar oxygenated functional group(s) in oxygenated lipids (ox-lipids) resulted in to their localization in the LD surface. We then explored possible interactions of ox-lipids with the heat shock protein 70 (HSP70), one of the key-proteins in antigen-cross presentation. Our data revealed that HSP70 specifically recognizes the neutral ox-lipids on the LD surface leading to tight binding and deep penetration into the phospholipid monolayer of the LD.

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inhibition mechanisms of lipoxygenases (LOX’s), the main generators of ox-lipids in ferroptosis cell death. We revealed the mechanism of peroxidation of esterified fatty acid via LOX’s and provided a possible mechanism of inhibition of LOX’s, particularly by vitamin E’s.

Lipid signaling due to asymmetric distribution of cardiolipin: The mitochondrial signature phospholipid, cardiolipin (CL), is asymmetrically distributed in the inner mitochondrial membrane. CL asymmetry is disrupted through a process called “CL externalization”, which can be recognized by many proteins. We described the molecular details of cardiolipin interactions with cytochrome c and LC3, the key players of apoptosis and mitophagy pathways, respectively.

The CL-binding site(s) on these proteins were identified. Our data suggested that the strong interactions of cyt-c/LC3 with CL-containing membranes lead to CL clustering. This clustering in turn induces a negative curvature on the membrane surface.

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LIST OF TABLES………………………………………………………………………………...x LIST OF FIGURES…………………………………………………………………………........xi ABBREVIATION…………………………………………………………………………..…...xvi ACKNOWLEDGEMENTS…………………………………………………………………......xix JOURNAL PUBLICATIONS……………………………………………………………………xx

1.0 CHAPTER 1: INTRODUCTION

1.1 BACKGROUND

1.1.1 Lipidome and Lipid Diversity

1.1.2 Lipid Signaling

1.1.2.1 Asymmetric distributions of lipids

1.1.2.2 Lipid modifications

1.2 OPEN QUESTIONS, GOALS AND ACCOMPLISHMENTS

1.2.1 Open Questions and Goals

1.2.2 Significance of the Study

1.2.3 Summary of Thesis Contributions

2.0 CHAPTER 2: APPROACHES

2.1 OVERVIEW

2.2 MOLECULAR DOCKING

2.2.1 Protein-Ligand Docking

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2.3 COARSE-GRAINED MOLECULAR DYNAMICS SIMULATIONS

2.3.1 Martini Force Field

2.3.2 Analysis of the CGMD trajectories





3.0 CHAPTER 3: COMPUTATIONAL STUDIES OF LIPID SIGNALING IN A TUMOR

ENVIRONMENT

3.1 SUMMARY

3.2 SIGNIFICANCE

3.3 INTRODUCTION

3.4 APPROACH

3.4.1 Setup and Optimization of CG Model of LD

3.4.2 CGMD Simulations of LD Containing oxTAGs

3.4.3 Study Interactions of oxLD and HSP70

3.5 RESULTS

3.5.1 Development of a CGMD Model for LD

3.5.2 Effects of Lipid Oxidation on Lipids Dynamics in LD

3.5.3 Interactions of Oxidized LD and HSP70

3.5.4 Comparison with Experimental Results

3.5.5 Discussion and Conclusions

4.0 CHAPTER 4: COMPUTATIONAL STUDIES OF LIPID SIGNALING IN

FERROPTOSIS

4.1 SUMMARY

4.2 SIGNIFICANCE

4.3 INTRODUCTION

4.3.1 Ferroptosis

4.3.2 Lipoxygenases

–  –  –

4.5 RESULTS AND DISCUSSIONS

4.5.1 LOX Catalytic Mechanism and Preferred Substrates

4.5.1.1 Role of R429 on oxygenated products

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4.5.2 Interactions of 15-LOX-2 and a ER-membrane Mimic

4.5.3 Can Inhibitors of Ferroptosis Potentially Inhibit LOXs?

4.5.3.1 Structures of ferroptosis/LOXs inhibitors

–  –  –

4.5.4 Tocotrienols Are More Effective Inhibitors of Ferroptosis Comparing Tocopherols

4.5.5 Comparison with Experimental Results

4.5.6 Discussion and Conclusion

5.0 CHAPTER 5: COMPUTATIONAL STUDIES OF CARDIOLIPIN SIGNALING IN

APOPTOSIS AND MITOPHAGY

5.1 SUMMARY

5.2 SIGNIFICANCE

5.3 INTRODUCTION

5.4 APPROACH

5.4.1 Effects of CL on the Structure and Properties of Lipid Membranes................ 90 5.4.2 Study Interactions of CL and Cyt-c

5.5 RESULTS AND DISCUSSIONS

5.5.1 Physical properties and functional roles of cardiolipin in membranes............ 93 5.5.2 Computational Studies of CL-signaling in apoptosis

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5.5.2.3 Coarse-grained molecular dynamics simulation of cyt-c interaction with membranes

5.5.2.4 Comparison with Experimental Results

–  –  –

5.5.3 Computational Studies if CL-signaling in mitophagy

5.5.3.1 LC3 structure and its conserved residues

–  –  –

6.0 CHAPTER 6: FUTURE DIRECTIONS

6.1 LIPID SIGNALING DUE TO OXYGENATION OF LIPIDS

6.1.1 Role of Oxygenated-Lipid-Containing Lipid Droplets in Cancer.................. 122 6.1.1.1 Structural role of ox-lipids in LD

6.1.1.2 Role of Oxygenated-Lipid-Containing Lipid Droplets in Antigen-Cross Presentation

6.1.2 Mechanism of Phospholipids Peroxidation in Ferroptosis

6.2 CL- SIGNALING DUE TO COLLAPSE OF ASYMMETRY

6.2.1 Interactions of CL and Proteins

BIBLIOGRAPHY

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Table 2-1 Thermodynamic properties of the CG particle types in MARTINI force field a [38].. 21 Table 3-1. LDs with four different lipid compositions and their shapes after 50 ns equilibration.

Table 3-2. Composition of LDs used to study the role ox-TAGs on LD structure via CGMD simulations.

Table 4-1 15LOX-2 molecular weight, isoelectric point and charge.

Table 4-2 The analysis of interacting lipids with NMBD of 15LOX-2.

Table 5-1 The composition of the membrane used for CGMD simulations of CL/cyt-c interactions.

Table 5-2 Residues interacting with CLs in each model, predicted by molecular docking.......... 99 Table 5-3 Residues interacting with CLs at t=1 μs for each individual CG-MD simulation..... 105 Table 5-4 Residues of LC3 in contact with CL during CGMD simulation.

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Figure 1-1 Relative distribution of lipids comparing other biological building blocks in human plasma.

Figure 1-2 Asymmetric distribution of CL between two leaflets induces membrane curvature, characteristic of the IMM and bacterial poles

Figure 1-3 Mitophagic translocation of cardiolipin: cardiolipin (CL) is synthesized by cardiolipin synthase (CLS) in the inner leaflet to of the IMM.

Figure 1-4 Predicted conformational models of oxidized choline glycerophospholipid inside the membranes, containing DMPC or DPPC/cholesterol.

Figure 2-1 MARTINI CG mapping of DPPC, cholesterol, and benzene. The prefix “S” denotes ring structures [38].

Figure 3-1 Lipid droplet structure.

Figure 3-2 Novel emerging roles of LDs in immunity.

Figure 3-3 Effect of POPC:TAG ratio on LD shape

Figure 3-4 CG-MD simulations of lipid droplets containing POPC in monolayer and TAG in the core, without any oxidized lipids (control system).

Figure 3-5 Initial and final configurations of LDs containing oxTAGs determine that significant amount of oxidized species move to the monolayer.

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Figure 3-7 Number density of oxTAG in systems containing dihydroxy-TAGs along the z-axis of the simulation box.

Figure 3-8 2D number density map of non-oxidized TAG molecules.

Figure 3-9 oxTAGs are located close to the surface, but below the head groups of POPC molecule.

Figure 3-10 Distance of center of mass (COM) of TAG/oxTAG to choline groups of POPC (LD surface) vs. time; in 5mol% truncated-TAG system, A. TAGs, B. oxTAGs

Figure 3-11 Molecular docking of truncated TAG to HSP70 domains.

Figure 3-12 Distance analysis of HSP70/oxLD trajectories.

Figure 3-13 HSP70 anchored on oxLD surface using a sheet-turn-sheet like domain................. 46 Figure 4-1 Ferroptosis is distinct from apoptosis, necrosis, and autophagy.

Figure 4-2 Ferroptosis is similar to glutamate-induced excitotoxicity.

Figure 4-3 Lipoxygenase phylogenetic tree.

Figure 4-4 Structure of human 15-LOX-2.

Figure 4-5 A comparison of the iron coordination environments for the mammalian LOXs...... 59 Figure 4-6 The general substrate peroxidation mechanism by LOXs [87].

Figure 4-7 Molecular docking data shows R429 is stabilized the tail in orientation of the substrate in the active site of 15LOX-2.

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Figure 4-9 A typical binding pose of (A) AA, (B) LA, (C) EPA and (D) DHA to 15LOX-2...... 66 Figure 4-10 AA and AdrA are equally susceptible to be peroxidized via 15LOX-2................... 66 Figure 4-11 The PLs mainly bind to 12 and 15LOX with relative high affinities

Figure 4-12 SA-PE and SAdr-PE are equally susceptible to be peroxidized via 15LOX-2......... 68 Figure 4-13 CGMD simulations of the interactions of 15LOX-2 with a ER-membrane mimic.. 69 Figure 4-14 The reconstructed predicted orientation of 15LOX-2 in the membrane —based upon CGMD simulations— to identify the location of the catalytic site opening versus surface of the membrane.

Figure 4-15 The hydrophobic analysis of the PLAT domain of 15LOX-2.

Figure 4-16 SAPI is the only PUFA-containing phospholipid in 15Å distance of the catalytic site of 15LOX-2.

Figure 4-17 The structures of ferroptosis/LOXs inhibitors.

Figure 4-18 The binding affinities of ferroptosis/LOXs inhibitors to human 15LOX-2.............. 78 Figure 4-19 Structures of tocopherols (Tp’s) and tocotrienols (Tt’s).

Figure 4-20 Molecular docking represent that the binding energies of all tocotrienol isoforms of vitamin E are lower —defining the higher affinity— comparing to corresponding isoforms of tocopherol (n=3).

Figure 4-21 Tocopherols and tocotrienols are equipotent inhibitors of 15LOX-2.

Figure 5-1 Cardiolipin is a diversified class of lipids.

xiii Figure 5-2: The illustration of CL-driven intracellular signaling pathways in mitophagy and apoptosis.

Figure 5-3 CG model of DOPC (left) and TOCL (right) molecules based on the MARTINI force field.

Figure 5-4 TMCL induces thickening and increasing the area per lipid head group in mixture with DMPC.

Figure 5-5 TOCL thickens the membrane and increases the average lipid area per head group in presence of DOPC as a matrix lipid in the bilayer

Figure 5-6 Cyt-c structure is a Heme containing protein localized in IMS.

Figure 5-7 Molecular docking predicts three CL-binding sites, which can be generalized in two main sites called “distal” and proximal” sites

Figure 5-8 The orientation of cyt-c with respect to the membrane predicted using OPM server.

Figure 5-9 Cyt-c interacts with higher affinity to the membrane containing a larger amount of CL.

Figure 5-10 Interactions of Cyt-c induce CL clustering on the membrane, which leads in a negative curvature on the membrane surface

Figure 5-11 Number of cyt-c residue interacting with membrane and number of CL interacting with cyt-c enhance by increasing CL concentration in the membrane, indicating higher affinity of cyt-c to interact with CL-rich membranes.

Figure 5-12 Two different autophagy pathways



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