SELF-ASSEMBLY AND DRUG DELIVERY IN AMPHIPHILIC PEPTIDES: MICROSCOPIC INSIGHTS FROM COARSE-GRAINED SIMULATIONS NARESH THOTA (M.Tech., IIT Roorkee) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2015 To My Parents, Teachers & Almighty God Declaration I hereby declare that the thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in this thesis. This thesis has also not been submitted for any degree in any university previously. _______________________ Naresh Thota May 2015 Acknowledgements First of all, I would like to express my sincere gratitude to my supervisor A/Prof. Jiang Jianwen for his constant guidance and support throughout my tenure of graduate studies. His technical advice and continuous motivation towards research inspired me to work diligently in achieving my targets in a punctual manner. I am very thankful to his guidance and support especially during the initial period of my research. The support he has shown on me during my ankle sprain injury was especially unforgettable. His guidance and suggestions will be definitely helpful to achieve my professional and personal aspirations. I am fortunate to work in his research group with highly technical and friendly environment. I am thankful to my lab mates for their helping nature and discussions in the lab. Specially, I want to thank Dr. Hu Zhongqiao and Dr. Luo Zhonglin for their help during the initial set up of my simulations. I am happy about working with other colleagues Dr. Anjaiah Nalaparaju, Dr. Chen Yifei, Dr. Fang Weijie, Dr. Krishna Mohan Gupta, Ms. Zhang Kang in the group. I would like to thank the internal and external examiners for spending precious time in examining my thesis and providing valuable comments. I am thankful to A/Prof. Yang Kun-Lin and A/Prof. Chen Shing Bor for being the panel examiners in my oral qualifying examination and thesis advisory committee. Their suggestions and comments were helpful in improving my research. I would also be grateful to the Department staff, including Vanessa, Sandy, Kwee Mei, Boey for their help during department administrative and i laboratory works. The scholarship provided by the National University of Singapore and the Ministry of Education, Singapore was really helpful for my study and research. I want to express special thanks to my roommates Srinath, Vamsi krishna, Naveen, Sanjeeva, Upendar Rao, Venkateshwara Reddy, Anil, Gopal, Shiva, Vinay for their help and special care, which were always positive, supportive and made me to stay healthily. I also want to thank my friends Chandu, Prakash, Ravi kiran, Siva, Praveen tej, Balaji for their positive words whenever I talked to them. I cannot forget to mention about my parents on this occasion whose love, affection, care and support made me to reach till this stage of my life. I specially want to mention my mother’s patience and help for my homework during school days. The discipline, hard work, patience and punctuality taught by my father made me strong to face all the circumstances with enough strength. I am happy to mention about my sister Kamala for her support and care throughout my life. I convey my gratitude to my uncle, aunts, siblings and cousins for sharing my happiness and sorrows with them. I would like to thank each and every teacher in my life because of their contributions in building my career. Finally, I want to thank his almighty God for giving this life, good health and strength. It would have been a dream to finish the PhD program without his blessings and kindness on me. Naresh Thota ii Table of Contents Acknowledgements i Table of Contents . iii Summary . vi List of Tables ix List of Figures x Abbreviations . xvi List of Symbols xvii Chapter 1. Introduction . 1.1 Background . 1.2 Amino Acids . 1.3 Applications 1.3.1 Antimicrobial Activities . 1.3.2 Nano Fabrication 1.3.3 Drug and Gene Delivery 10 1.3.4 Cosmetic and Skin Care Applications . 11 1.3.5 Other Applications . 11 1.4 Objectives and Scope of the Thesis 13 Chapter 2. Literature Review 15 2.1 Surfactant-Like Peptides . 15 2.2 Lipid-Based Peptides 20 2.3 Amphiphilic Peptides 25 Chapter 3. Simulation Methodology . 30 3.1 MARTINI Model 30 3.2 Molecular Dynamics Simulation 34 iii Chapter 4. Self-Assembly of Short Amphiphilic Peptides FmDn and FmKn . 36 4.1 Introduction . 36 4.2 Models and Methods . 38 4.3 Results and Discussion . 43 4.3.1 FmD and FmK Peptides . 44 4.3.2 F3Kn and F6Kn Peptides 47 4.4 Conclusions . 57 Chapter 5. Self-Assembly of Amphiphilic Peptide (AF)6H5K15 59 5.1 Introduction . 59 5.2 Models and Methods . 61 5.3 Results and Discussion . 64 5.3.1 Effect of Box Size 64 5.3.2 Effect of Peptide Concentration . 72 5.4 Conclusions . 76 Chapter 6. Self-Assembly of FA32 Derivatives: Roles of Hydrophilic and Hydrophobic Residues 78 6.1 Introduction . 78 6.2 Models and Methods . 80 6.3 Results and Discussion . 82 6.3.1 Length of Hydrophilic Residues 82 6.3.2 Replacement of Ala by Phe Residues 89 6.3.3 Length of Hydrophobic Residues 92 6.4 Conclusions . 97 iv Chapter 7. Ibuprofen Loading and Release in FA32and its Derivatives . 99 7.1 Introduction . 99 7.2 Models and Methods . 102 7.3 Results and Discussion . 106 7.3.1 IBU Loading in FA32 107 7.3.2 IBU Loading in F12H5K15 and F16H5K15 114 7.3.3 IBU Release . 116 7.4 Conclusions . 119 Chapter 8. Effects of Peptide Sequence on Self-Assembly and Ibuprofen Loading 121 8.1 Introduction . 121 8.2 Models and Methods . 122 8.3 Results and Discussion . 124 8.3.1 Effect of Peptide Sequence on Assembly 124 8.3.2 Effect of Peptide Sequence on IBU Loading . 129 8.4 Conclusions . 131 Chapter 9. Conclusions and Recommendations . 132 9.1 Conclusions . 132 9.2 Recommendations for Future Studies . 135 Bibliography 138 Journal Publications . 149 Conference Presentations . 150 v Summary Amphiphilic peptides are biodegradable and biocompatible, important characteristics for ideal drug carriers. They can form nano-sized micelles with hydrophobic cores allowing for encapsulation of hydrophobic drugs, and thus provide an effective protection against hydrolysis and degradation. In addition, the size, stability, permeability and elasticity of the micelles can be fine-tuned by tailoring peptide sequence, length, solution conditions, etc. The micelles may undergo structural transition triggered by pH variation or other stimuli leading to drug release. Therefore, amphiphilic peptides have received considerable interest for drug delivery. Nevertheless, there is no theoretical guidance currently available on the rational selection and design of amphiphilic peptides to achieve optimal drug delivery. Through molecular dynamics simulation, the objective of this thesis is to quantitatively understand the self-assembly behavior of amphiphilic peptides from a microscopic scale, elucidate the detailed process of drug loading and release, and provide bottom-up guidelines towards the intelligent design of new amphiphilic peptides for drug delivery. The main contents of the thesis contain four parts. (1) Self-assembly of short amphiphilic peptides FmDn and FmKn is examined. Within s-scale simulation, FD and FK only form loose polymeric clusters. Upon increasing the length of Phe residues in FmD and FmK (m = to 4), larger and more stable micelles are formed. FmK and FmD prefer to assemble into quasi- vi spherical and sheet-like micelles, respectively. For F3Kn (n = to 8) and F6Kn (n = to 12), the assembly capability reduces leading to smaller micelles when the length of Lys residues increases. For the formation of quasi-spherical micelles with distinct core/shell structure, the optimal ratio of hydrophobic/hydrophilic residues is found to be 3/4 for both F3Kn and F6Kn. (2) A relatively longer amphiphilic peptide FA32 [(AF)6H5K15] is studied. Spherical micelles are formed, with Ala and Phe in hydrophobic core, Lys in hydrophilic shell and His at core/shell interface. The assembly process and microscopic structures are analyzed in terms of the number of clusters, the radii of micelle, core and shell and the density profiles of residues. It is found that the micellar structures and microscopic properties are essentially independent of the size of simulation box. With increasing concentration, quasi-spherical micelles change to elongated shape and micelle size generally increases. (3) The effects of hydrophilic and hydrophobic chain lengths on self-assembly are studied. With increasing length of hydrophilic Lys residues in (AF)6H5Kn (n = 10, 15, 20 and 25), the assembly capability is reduced by forming smaller micelles or the presence of individual peptide chains. Upon replacing Ala by more hydrophobic Phe in AmFnH5K15 (m + n = 12), larger micelles are formed. With increasing length of hydrophobic Phe residues in FnH5K15 (n = 4, 8, 12 and 16), micelle size increases and the morphology shifts from spherical to fiber-like. (4) A model hydrophobic drug, ibuprofen (IBU), is investigated for loading and release in FA32, F12H5K15 and F16H5K15. Upon the loading of IBU in FA32, quasi-spherical core/shell structured micelles are formed. IBU is predominantly vii Chapter 9. Conclusions and Future Recommendations governing factors such as chain length, hydrophobicity and sequence have been identified. The simulation findings would facilitate the design of new amphiphilic peptides for tuning morphology and high-efficacy drug delivery. 9.2 Recommendations for Future Studies As an extension of the simulation studies presented in this thesis, the recommendations for future studies are suggested below.  In Chapter 4, short amphiphilic peptides based on phenylalanine, lysine and aspartic acid are examined. Particularly, phenylalanine containing an aromatic side chain turns out to be important for assembly. A few other amino acids also contain similar aromatic side chain, e.g., tyrosine and tryptophan. They can be connected with charged hydrophilic amino acids such as glutamic acid and arginine to form various short peptides. It would be interesting to further examine these peptides, and tune the ratio of hydrophobic/hydrophilic residues towards desired morphologies.  In Chapters and 8, spherical micelle and nanofiber are investigated for the loading and release of ibuprofen. However, other morphologies (e.g. vesicles) can also form by tuning peptide length, cyclic structure, replacement of charged residues, etc.197-200 Vesicles are capable to deliver both hydrophobic and hydrophilic drugs. It should be noted, however, simulation box must be sufficiently large to allow vesicles to form.201 In addition to ibuprofen, other drugs like doxorubicin (DOX) and paclitaxel (PTX), or multi-drug could be studied. Nevertheless, appropriate force fields for these drug molecules should be developed first as they are not available in the MARTINI model. 135 Chapter 9. Conclusions and Future Recommendations  The amphiphilic peptides in this thesis contain solely amino acids. As introduced earlier, other types of peptides such as lipid-like (carbon chains or lipid tails attached to hydrophilic amino acids)202 can be simulated. The lipid tails have tendency to form β-sheet structures, thus a combination of secondary structure (by lipid tails) and random coils (by amino acids) can be utilized to design new lipid-like peptides. Furthermore, the length of lipid tails is readily tunable to generate the required morphologies for specific application of interest.203  In practical drug delivery, a carrier first encapsulates drug, passes through cell membrane, then releases drug. In this thesis, the loading and release of ibuprofen in FA32 peptide and its derivatives are simulated in an aqueous medium. Possible future studies are to examine the interactions of drug-loaded peptides with bilayers or vesicles (as models for cell membranes).204 However, such simulation studies require extra-large computational resources.  The MARTINI model has a limitation to mimic secondary structure transition during simulation.205 In this thesis, all the peptides are assumed to be random coiled. However, it is intriguing to explore the effect of secondary structure on self-assembly and assembled structures. The proper length and variation of secondary structures from experimental studies206 on other systems can be utilized as a guidance to kick off such further studies.  Though simulations are accelerated by coarse-grained models, atomistic details such as hydrogen bonding cannot be easily quantified. To overcome this, coarse-grained models can be reversed back to atomistic structures and 136 Chapter 9. Conclusions and Future Recommendations thus provide more microscopic information.207 Alternatively, multiscale descriptions can be adopted for peptide and water molecules. For example, peptide is represented by atomistic model whereas water is mimicked by coarse-grained model. By doing this, simulation is accelerated and atomistic details of peptide are preserved. The MARTINI model allows such hybrid simulation208 and can be applied in future studies.  The dynamic properties including cluster size and morphology transition as a function of time, drug loading and release processes are studied using MD simulations in this thesis. The kinetic data such as diffusivity of IBU in the micelles cannot be calculated by the common MD method used here, which can be determined by applying transition-state theory.  Our simulation reveals that a ratio of ¾ phenylalanine to lysine residues favors the formation of spherical micelles. The same ratio may be utilized to design other amphiphilic peptides (e.g. F3K4, F6K8, F9K12). These peptides could be studied experimentally to examine their morphologies.  Peptide F16H5K15 forms elongated micelles but uniform fibers upon the loading of drug molecules. 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Naresh Thota, Zhonglin Luo, Zhongqiao Hu, and Jianwen Jiang, SelfAssembly of Amphiphilic Peptide (AF)6H5K15: Coarse-Grained Molecular Dynamics Simulation, Journal of Physical Chemistry B, 2013, 117, 96909698. 149 Conference Presentations 1. Naresh Thota and Jianwen Jiang, Self-Assembly of Amphiphilic Peptide (AF)6H5K15: Roles of Hydrophobic and Hydrophilic Residues, AIChE Annual Meeting 2014, Atlanta, USA. 2. Naresh Thota, Zhongqiao Hu and Jianwen Jiang, Ibuprofen Loading and Release in Micelles Formed by Amphiphilic Peptide (AF)6H5K15: A CoarseGrained Molecular Dynamics Simulation, AIChE Annual Meeting 2014, Atlanta, USA. 3. Naresh Thota, Zhonglin Luo, Zhongqiao Hu and Jianwen Jiang, Molecular Dynamics Simulation for Self-Assembly of an Amphiphilic Peptide, ICMAT 2013, Singapore. 150 [...]... on IBU loading are investigated in (AF)6H5K15, H5(AF)6K15, H5K5(AF)6K10 and (AF)3H5K15(AF)3 It is revealed that peptide sequence has an insignificant effect on drug loading From this thesis, microscopic insights into the self- assembly of amphiphilic peptides, and the loading and release of drug are provided Equilibrium and dynamic properties are obtained from a molecular level Key governing factors... atom of amine group in the other amino acid Peptides usually consist of 2-50 amino acids, and long chains of peptides are known as proteins There are 20 naturally occurring amino acids (see Figure 1.3) utilized in the synthesis of peptides and proteins in biological cells.26 Therefore, 3 Chapter 1 Introduction almost unlimited number of peptides can be formed with various arrangements and combinations... provide microscopic insights that otherwise are experimentally 13 Chapter 1 Introduction inaccessible or difficult to obtain, and thus assist in the rational screening and design of novel peptides The objective of this thesis is to quantitatively understand the self- assembly of amphiphilic peptides with various hydrophobic and hydrophilic moieties, elucidate the detailed process of drug loading and release,... designed and synthesized such peptides from a C16 tail and a peptide containing cysteine residues The self- assembled nanofibers were robust and pH invariant due to the 8 Chapter 1 Introduction presence of disulfide bonds, and useful in mineralization of hydroxyapatite.34 In another study, they attached a C16 chain to various sequences of peptides that formed cylindrical nanofibers with peptide sequences in. .. box, (b) 26 peptides in 15 nm box, and (c) 44 peptides in 18 nm box 69 Figure 5.6 Distributions of Rmicelle for (a) 10 peptides in 11 nm box (b) 26 peptides in 15 nm box (c) 44 peptides in 18 nm box 70 Figure 5.7 Density profiles of micelles for 26 peptides in 15 nm box The micelles contain 10, 8, and 8 peptides in (a), (b), and (c), respectively 71 Figure 5.8 Final snapshots... reported in the literature on the self- assembly of peptides The peptides examined can be categories into three types: surfactant-like peptides that appear like surfactants with charged hydrophilic amino acids connected to hydrophobic residues; lipidbased peptides in which carbon chains act as hydrophobic tails and are attached to amino acids; and amphiphilic peptides in which both hydrophobic and hydrophilic... drugs, immediate treatment is still lacking due to the high cost of drugs.50,51 It is economically more feasible to develop better delivery method for existing drugs rather than inventing new drugs Current delivery materials such as surfactants and copolymers have been tested and few of them are in clinical trials;52-57 however, the instability and toxicity impede their popular use.58 Amphiphilic peptides. .. materials for drug delivery They were tested for delivering drug or gene or both, and better therapeutic effects were found on cancer cells or genetic disorders.14 In addition, a wide variety of peptides were examined for assembly1 5, drug delivery1 6, gene delivery1 4, anti-microbial activity17 Every year, about 17 new peptides enter into clinical studies and about 140 peptides are currently in the development... release, and provide bottom-up guidelines towards the intelligent design of new amphiphilic peptides for high-efficacy drug delivery The thesis is organized in nine chapters Chapter 1 describes the basic properties of amino acids, the applications of peptides and the scope of the thesis Chapter 2 summarizes the existing studies on surfactant-like peptides, lipid-based peptides and amphiphilic peptides. .. performance The morphologies depend on the interactions between peptides, as well as between peptides and 12 Chapter 1 Introduction guest molecules Fundamental understanding of self- assembly process is thus critical to the screening and design of ideal peptides for specific applications 1.4 Objectives and Scope of the Thesis There has been continuous increase in the incidence and mortality rate of cancer for . an insignificant effect on drug loading. From this thesis, microscopic insights into the self- assembly of amphiphilic peptides, and the loading and release of drug are provided. Equilibrium and. SELF- ASSEMBLY AND DRUG DELIVERY IN AMPHIPHILIC PEPTIDES: MICROSCOPIC INSIGHTS FROM COARSE- GRAINED SIMULATIONS NARESH THOTA (M.Tech., IIT. process of drug loading and release, and provide bottom-up guidelines towards the intelligent design of new amphiphilic peptides for drug delivery. The main contents of the thesis contain four