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Protocol Optimization of Molecular Dynamics Simulations of Apolipoproteins

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Protocol Optimization of Molecular Dynamics Simulations of Apolipoproteins BUILDING BETTER MODELS: PROTOCOL OPTIMIZATION OF MOLECULAR DYNAMICS SIMULATIONS OF APOLIPOPROTEINS A THESIS Presented to the University Honors Program California State University, Long Beach In Partial Fulfillment of the Requirements for the University Honors Program Certificate Yessica K. Gomez Fall 2016 ABSTRACT BUILDING BETTER MODELS: PROTOCOL OPTIMIZATION OF MOLECULAR DYNAMICS SIMULATIONS OF APOLIPOPROTEINS By Yessica K. Gomez December 2016 Apolipoproteins are biologically-ubiquitous lipid transport proteins that have been implicated in the onset of Alzheimer’s disease and serve as a target for therapies focused on drug delivery to the brain. Their distinct topology and electrostatic makeup have contributed to the lack of computational chemistry studies on them. In this study, we report a many-microsecond data set comprising a variety of molecular dynamics simulations meant to probe the effects of varying force field, long-range electrostatics, and cut-off distances on three different apolipoprotein structures. The results display a clear consensus on the ideal settings to recreate biological conditions, with all three structures exhibiting the best behavior using the AMBER-94 force field with particle mesh Ewald (PME) and mid-range cut-off distances. These results are in line with previous force field studies and will serve as an initiation point for future high-temperature unfolding studies that will provide new details regarding the mechanics of the folding pathway. ACKNOWLEDGEMENTS My initial thanks goes to Dr. Sorin, without whose mentoring and resources this project would not have been possible. Thank you as well to all the members of the Sorin Lab I have worked with over the past three years – particularly Dakota and Xavier – and all others who collaborated with me on this project. I wish to acknowledge the University Honors Program, especially Kashima and Lizette, for their academic advice, and help in getting me through the program, and Dr. Thien, who was an excellent and knowledgeable 498 instructor. Additional thanks to all the friends I made in the UHP: your encouragement and empathy has been invaluable while writing this thesis. Finally, thanks to my family, whose unwavering support over the course of my academic career has gotten me where I am today. I am eternally grateful for everything you have given me and sacrificed alongside me, especially in the four years over which this project was developed and completed. iii TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ......................................................................................... iii LIST OF TABLES ....................................................................................................... vi LIST OF FIGURES ..................................................................................................... vii LIST OF ABBREVIATIONS ...................................................................................... viii CHAPTER 1. INTRODUCTION ............................................................................................ 1 Apolipoproteins.......................................................................................... 1 Molecular Dynamics .................................................................................. 4 2. METHODS ....................................................................................................... 8 Choosing MD Parameters .......................................................................... 8 MD Simulations ......................................................................................... 11 3. RESULTS AND DISCUSSION ....................................................................... 13 Results ........................................................................................................ 13 Discussion .................................................................................................. 14 Conclusion ................................................................................................. 16 APPENDIX…… .......................................................................................................... 18 REFERENCES ............................................................................................................ 22 iv LIST OF TABLES TABLE Page 1. Final list of parameters chosen for comparison ................................................ 10 2. Most ideal parameters for apolipoprotein simulation ...................................... 14 3A. Differences in native state structural behavior based on initial parameters For 1LS4 ................................................................................................. 19 3B. Differences in native state structural behavior based on initial parameters For 2KC3 ................................................................................................ 20 3C. Differences in native state structural behavior based on initial parameters For 2L7B ................................................................................................. 21 v LIST OF FIGURES FIGURE Page 1. Size classes and composition of lipid micelles in humans ............................... 2 2. Starting structures for all three apolipoproteins ................................................ 9 3. Time-dependent fluctuation of RMSD and radius of gyration ......................... 13 vi LIST OF ABBREVIATIONS Apo E Apolipoprotein E Apo III Apolipophorin III BAPP Beta amyloid precursor protein CT Carboxyl terminus NT Amino terminus MD Molecular dynamics RMSD Root mean square deviation PME Particle mesh Ewald RF Reaction-field VDW Van der Waals SS Steady-state DSSP Hydrogen bond estimation algorithm AMBER Assisted Model Building with Energy Refinement vii CHAPTER 1 INTRODUCTION Apolipoproteins Apolipoproteins are a diverse class of alpha-helical lipid transport proteins ubiquitous in the human body1. They are also found in other animals, such as insects, where they serve different structurally-mediated roles. Natively, they exist in an unbound, free-floating conformation where the helices bundle themselves together so the hydrophobic faces are hidden away from the surrounding water2. Most commonly, these bundles are found in small groups of around four, although additional helices may be present to serve as wrappers or tails. Discovery of apolipoproteins began in the seventies3, and from there, it was quickly apparent that many different apolipoprotein families exist. In humans, there are currently six main classes: A-E and H. Each class is affiliated with transporting one or more different types of lipid micelle, which is a spherical amphipathic monolayer enclosing many free-floating cholesterol and lipid (fat) molecules4. A cutaway demonstrating the contents of these lipid micelles is shown Figure 1b. When bound to a lipid package known as a micelle, the apo- prefix is dropped and they are simply referred to as lipoproteins. The association of activated lipoproteins with corresponding micelles is a physical transformation in which the native state opens up via some unfolding mechanism, the mechanics of which is still in contention among researchers5-7. This behavior is also illustrated when the protein attaches to a signal receptor, triggering some response within the cell2. Once bound, the lipid-protein complex can travel through the body via 1 either the lymphatic or circulatory system. In addition, each apolipoprotein family is also associated with a particular organ or organs within the body. For example, the apolipoprotein E (apo E) family is associated primarily with transporting the chylomicron and low-density (LDL) classes of micelle to and from the brain8. Figure 1. Size classes and composition of lipid micelles in humans. (a) Micelles are classified by density, and can be referred to as high, low, very low, or chylomicron. The lipoprotein wraps around the micelle via hydrophilic interactions with the polar lipid membrane heads. (b) The cutaway diagram demonstrates the variety of cholesterol and lipid molecules that rely on apolipoprotein association for proper transport8. Apolipoprotein E Apo E is especially important because its main transport location means it can cross the blood brain barrier, a highly selective semi-permeable membrane that protects the central nervous system from the circulatory system2. This unique feature has made it the focus of a multitude of scientific studies that have allowed its other, equally interesting characteristics to come to light. It is now known that apo E exists in three separate genotypes: apo E2, apo E3, and apo E4, which can appear in any combination with each other depending on which two alleles a human has for the protein. While the structures of these isoforms vary by only a single nucleotide each, their biological function is extremely different9. Mutations in apolipoprotein E 2 genotype, specifically from apo E2 or E3 to apo E4, have been correlated with improper interactions with amyloid beta peptides via the beta amyloid precursor protein (BAPP)10. These peptides are one of the precursors for fatty plaques in the brain, creating a strong link between these unfavorable contacts and the development of blood vessel-based diseases of the brain and heart, such as atherosclerosis, dementia, and Alzheimer's. Alzheimer's Disease. Alzheimer's disease (AD) is a neurodegenerative disorder that manifests itself as a progressive loss of memory and psychological control. It affects people worldwide, yet there is currently no cure.
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