低溶血高抗菌之Indolicidin類似胜肽的分子設計-以分子模擬與螢光測定為輔助工具

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蔡經緯(Ching-Wei Tsai) 查詢紙本館藏

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化學工程與材料工程學系

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低溶血高抗菌之Indolicidin類似胜肽的分子設計-以分子模擬與螢光測定為輔助工具
(Molecular Design of Less Hemolytic and Highly Antibacterial Indolicidin-Derived Peptides Assisted by Molecular Simulation and Fluorescence Analysis)

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摘要(中)

Indolicidin (IL)為13個胺基酸組成且富含色胺酸之鹼性抗生胜肽，對於許多病原體具有良好的抗生活性，因此具有相當的潛力成為新一代的抗生藥物。可惜的是IL的溶血活性限制了它在臨床醫學的測試，故許多學者把研究的焦點放在如何有效地設計同時具有高抗菌活性且低溶血活性的IL類似物，但是都還未能得到具有這種潛力的IL類似胜肽，僅止於獲得抗菌能力與IL相同但溶血有大幅下降的IL類似胜肽。許多研究指出IL的生物活性與其和磷脂膜之間的交互作用有關，由於細菌與血球的磷脂膜組成不同，因此推測IL對於這兩種細胞膜的擾亂程度亦會有所不同；另一方面，也有學者提出IL胜肽會於水中形成聚集物，並且發現聚集物的形成與其溶血性息息相關。我們認為若能得知影響抗菌溶血關鍵之胺基酸，則可設計一條新的IL類似物，改善其溶血性並增加其抗菌性。因此本研究首先以全原子動態模擬 (all-atom molecular dynamics simulation) 探討IL分別和仿細菌細胞膜與仿血球細胞膜的作用過程中，影響磷脂膜擾亂的關鍵胺基酸。一方面以微觀分子尺度來了解IL與磷脂膜的交互作用機制；另一方面也可以準確地置換造成溶血的胺基酸與增加造成抗菌的關鍵胺基酸。如此一來希望可以設計一條低溶血性且高抗菌性的IL類似胜肽。接著針對設計的抗生肽進行螢光光譜的量測與分析，探討IL類似胜肽是否會產生聚集，進一步的探討聚集物和磷脂膜交互作用的機制。最後結合螢光光譜與分子動態模擬的分析，希望能提出設計低溶血高抗菌IL類似胜肽的關鍵因素。
首先，以分子動態模擬探討IL與兩種磷脂雙層膜的交互作用，其中使用電中性的磷脂質POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) 來模仿紅血球的細胞膜；以3比1的比例混合POPC與帶負電荷磷脂質POPG (1-palmitoyl- 2-oleoyl-sn-glycero-3-phosphoglycerol) 則是用來模仿細菌的細胞膜。為了清楚觀察IL與兩種磷脂雙層膜作用的吸附階段與插膜階段的行為，總模擬時間一共花費4 ?s。進一步的以磷脂質親水頭基的分佈情形和疏水區的排列整齊度來了解磷脂膜受IL作用後的擾亂程度，結果發現當IL吸附於POPG/POPC混合膜時就會造成顯著的膜擾亂。而對POPC膜來說，IL在吸附階段造成的膜擾亂較小，但在穩定插膜階段則較為顯著。由上述結果，若增強IL對細菌膜的吸附程度可以增強其抗菌性，而抑制IL插入至血球細胞膜的疏水核心可降低其溶血性。進一步地分析在吸附和穩定插膜階段造成膜擾亂的關鍵胺基酸後，設計出三條低溶血之IL的類似物：IL-K7 (Pro7?Lys)、IL-F89 (Trp8 & Trp9 ?Phe)與IL-K7F89(Pro7?Lys, Trp8 & Trp9 ?Phe)，其中IL-K7F89為最低溶血且還具有比IL還要強一倍的抗菌活性，這是由於同時降低了胜肽的疏水性與增加了胜肽的帶正電性。此外也進行IL-F89與兩種磷脂雙層膜的動態模擬來驗證是否膜擾亂與生物活性有關，結果發現IL-F89確實會降低仿血球細胞膜的擾亂且對於病菌細胞膜的擾亂程度和IL差異不大，因此本研究認為膜擾亂與其生物活性確實有高度的正相關。所以分子動態模擬的方法對研究如何設計低毒性的抗生胜肽來說不失為一利器。
另一方面，為了了解IL及其類似物是否在水相環境也會形成聚集物與聚集物對生物活性所造成的影響，首先由胜肽螢光強度之測量與丙烯醯胺 (acrylamide) 螢光淬滅實驗結果分析出胜肽在水溶液中會因疏水作用力而聚集，且IL及其類似物的聚集體大小不一。進一步地探討IL及其類似物與仿細菌膜與仿血球細胞膜的作用，其中包含胜肽在膜上之吸附量、胜肽插膜的深淺與胜肽聚集體在膜內的分散程度，希望能找到影響抗生胜肽生物活性之指標，這樣子即能提供設計抗生藥物的關鍵因素。另外也發現，降低胜肽疏水性會減弱其在仿血球細胞膜上之吸附與插膜深度，也因此降低了其溶血活性。另一方面，雖然增加胜肽之靜正電荷會使其抗菌活性上升，但卻不是影響胜肽與膜結合的主因，而是幫助胜肽聚集體更能在負電荷細菌細胞膜上分散。所以推論胜肽聚集行為與其在膜上的分散行為是主導IL及其類似物抗菌活性的因素。
本研究希望能夠藉由分子動態模擬並結合螢光實驗的分析探討胜肽與細胞膜的交互作用機制，歸納出設計抗菌胜肽之關鍵。綜合模擬與螢光實驗的結果發現胜肽的帶電性與疏水性的大小與其擾亂膜的能力有直接相關，特別是由螢光光譜分析而得知抗生肽的聚集體在仿病菌細胞膜的分散與抗菌活性直接相關，這確實在於如何設計一條低毒性與高抗菌性抗生肽方面是一重大發現。

摘要(英)

Indolicidin (IL), a naturally synthesized peptide from bovine neutrophils, is a tryptophan-rich cationic antimicrobial peptide composing of only 13 amino acids. It is effective against a broad spectrum toward many kinds of pathogens. Therefore, it is regarded as a potential new-generation peptide antibiotic. However, similar to most antimicrobial peptides, indolicidin suffers from its possible disruption of erythrocytes. Recently, many researchers have paid much attention to design an IL-analogue with high antimicrobial activity but low hemolytic activity for applying in therapy, Systematically changing each amino acid in sequence has been tried to obtain an IL-analogue with high antimicrobial but low hemolytic activity. Limited success was obtained. A lot of efforts were then put into understanding the bactericidal and hemolytic mechanisms of indolicidin. Rational design can be taken after these mechanisms are understood. Many mechanisms have been proposed. Most of them were related to membrane kperturbation. We conjectured that IL peptide may perturb bacteria and erythrocyte cells with different extents arisen from the difference of the membrane compositions. We then try to evaluate the importance of each amino acid in sequence through the help of molecular dynamics simulation. Three IL analogues owning different antibacterial and hemolytic activities are designed by altering the important positions. Besides, it has been found that the aggregation of IL peptide in aqueous phase is related to its hemolysis. Furthermore, the fluorescence measurement and analysis were used to investigate whether the designed IL-analogues would form aggregates in aqueous solution or not and further investigated the actions of aggregative peptide-membrane interaction to evaluate the relationships between peptide structure and membrane perturbation. Criteria for peptide design can then be obtained.
The all-atom molecular dynamics simulation of interaction of IL peptide and two model lipid bilayers were performed with total simulation time up to 4??s to reveal the processes of IL adsorption onto and insertion into the membranes. The zwitterionic phospholipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), were used to mimic mammal cell membrane. The bacterial cell membrane was modeled by the mixture of POPC and negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphoglycerol (POPG). The packing order of lipid bilayer and the distribution of hydrophilic heads of phospholipids were presumably correlated to the membrane stability. It was found that the order of the mixed POPG/POPC lipid bilayer is reduced significantly upon the adsorption of IL. On the other hand, the order of the pure-POPC lipid bilayer is perturbed only slightly during the adsorption stage, but greatly reduced during the insertion stage. The results implied that the enhancement of IL adsorption on the microbial membrane may amplify its antimicrobial activity, while hemolysis may be reduced by the inhibition of IL insertion into the hydrophobic region of erythrocyte membrane. Three lower hemolytic IL-analogues including IL-K7 (Pro7 ? Lys), IL-F89 (Trp8 & Trp9 ? Phe) and IL-K7F89 (Pro7 ? Lys, Trp8 & Trp9 ? Phe) were further design from the analysis of critical amino acids in membrane perturbation. Moreover, the simulations of interaction between IL-F89 peptide and two model lipid bilayers were performed to discuss the relationships between membrane perturbation and biological activity. The results suggested that the perturbation of the hydrophobic core of lipid bilayer by single peptide is strongly related to its biological activities. Therefore, the molecular dynamics simulation of peptide-model membrane interaction successfully facilitated to design a peptide with higher antibacterial and at the same time lower cytotoxicity.
Moreover, the structure-activity relationships of indolicidin and its analogues were investigated through their interactions with the bacterium-like and erythrocyte-like model membranes. The intrinsic fluorescence and acrylamide quenching analysis were used to examine three designed IL-analogues would form aggregates in aqueous solution or not, and the results revealed that these peptides aggregate into different sizes in solution by hydrophobic interaction. The amounts of the peptide adsorption to model membrane, relative insertion depth of peptide in membrane, and degree of peptide aggregates dispersion in membrane, were defined to connect the peptide actions toward the model membranes to the bioactivities of the peptides. In particular, the roles of peptide aggregation to its bioactivities were interpreted. It was found that the reduction of peptide hydrophobicity reduces the peptide adsorption and insertion of peptides to the erythrocyte-like membrane. Subsequently, the hemolytic activity is reduced. On the other hand, the increase in peptide electropositivity would enhance the antibacterial activities. But the increase in electropositivity does not necessarily increase peptide-membrane binding. Instead, the peptide hydrophobicity facilitates aggregate formation in aqueous solution and the role of positive charges is to assist aggregate dissembling in the negatively charged bacterium-like membranes. Therefore, the peptide aggregation in solutions and dissembling in membranes play important roles in the antibacterial activity of indolicidin and its analogues.
By coupling the molecular dynamics simulations and experimental data analysis, this study proposed a new insight based on the peptide-membrane interaction for antimicrobial peptide design. The peptide electropositivity and hydrophobicity is highly related to membrane perturbation, in particular, the finding of peptide aggregates with higher electropositivity dispersing in electronegative bacterium-like membrane is a major reason to cause the higher antibacterial activity. Therefore, the tuning of peptide hydrophobicity and electropositivity for peptide aggregates in aqueous phase is an important implication for potential antibacterial peptide design.

關鍵字(中)

★ indolicidin
★ 鹼性抗生肽
★ 抗生肽藥物設計
★ 分子動態模擬
★ 螢光光譜分析

關鍵字(英)

★ fluorescence analysis
★ molecular dynamics simulation
★ indolcidin
★ cationic antimicrobial peptide
★ peptide drug design

論文目次

ABSTRACT (CHINESE) I
ABSTRACT (ENGLISH) III
ACKNOWLEDGMENTS III
LISTS OF FIGURES X
LISTS OF TABLES XII
CHAPTER 1. INTRODUCTION 1
1.1. Research Motivation and Purposes 1
1.2. Overview of This Thesis 5
CHAPTER 2. LITERATURE SURVEY 6
2.1 Research Background 6
2.1.1. Characteristics of CAPs 6
2.1.2. Biological Activities of CAPs 8
2.1.3. Proposed Mechanisms of CAPs Action 8
2.1.4. Tryptophan-Rich Antimicrobial Peptide Indolicidin 13
2.1.4.1. Characteristics of Indolicidin 13
2.1.4.2. Lower Cytotoxicity Indolicidin-Analogues Design 14
2.2. Fluorescence Analysis of Peptide-Membrane Interaction 16
2.3. Molecular Dynamics Simulation 18
2.3.1. Background of MD Simulation 18
2.3.2. MD Simulation of Peptide-Membrane Interaction 24
CHAPTER 3. MATERIALS AND METHODS 26
3.1. MD Simulation Methods 26
3.1.1. System Building 26
3.1.2. Force Field and Simulation Setup 27
3.1.3. Simulation Analysis 28
3.1.3.1. Membrane Ordering 28
3.1.3.2. Minimum Salt Bridge Distance 28
3.2. Experimental Methods 29
3.2.1. Chemical Compounds and Biomolecules 29
3.2.2. Measurements of the Bioactivities of IL and Its Analogues 29
3.2.3. Preparation of SUVs 30
3.2.4. Fluorescence Spectra Measurements 31
3.2.5. AAm Quenching of Peptides in PBS Buffer 31
3.2.6. Dual-functional Fluorescence Quenching Assays 32
3.2.7. CD Measurements 32
3.2.8. Peptide-SUVs Equilibrium Dialysis Measurements 33
3.2.9. Quantification of Intrinsic Fluorescence of Peptides in SUVs 33
3.2.10. Dispersion Index of Peptides in Aqueous Solution 34
3.2.11. Dispersion Index of Peptides in SUVs 34
3.2.12. Dispersion Index and Depth Index of Peptides in SUVs 34
CHAPTER 4. MD SIMULATIONS FOR IL-ANALOGUES DESIGN 36
4.1. Equilibrium of Two Model Lipid Bilayers 36
4.2. IL-Model Membranes Interaction 37
4.2.1. IL-POPC Lipid Bilayer Association 37
4.2.2. IL–Mixed POPG/POPC Lipid Bilayer Association. 39
4.2.3. Definitions of Adsorption and Stable Insertion Stages. 40
4.2.4. IL-Mediated Lipid Bilayer Disordering. 41
4.2.5. Critical Amino Acids for the Disordering of Lipid Bilayer. 44
4.4. Antimicrobial and Hemolytic Activities of Designed Peptides. 50
4.5. MD simulation of IL-analogues with Model Lipid Bilayer 54
CHAPTER 5. ACTION OF CAPS-MEMBRANE ASSOCIATION 56
5.1. Aggregation of IL-Analogues in Aqueous Solution 56
5.1.1. Determination of aggregation of IL-Analogues 57
5.1.2. Driving Force of Peptide Aggregation 59
5.2. IL-analogues and Model Membranes Interactions 60
5.2.1. Amounts of IL-analogues Adsorption to Model Membranes 61
5.2.2. Degree of Peptide Dispersion within the Model Membranes 62
5.2.3. Insertion Depth of IL-Analogues in Model Membrane 63
5.3. Implications on Cationic Antimicrobial Peptide Design 64
CHAPTER 6. CONCLUSIONS 67
FIGURES 70
TABLES 94
REFERENCES 97
APPENDIX-PUBLICATION LISTS 112
2.1.1. Characteristics of CAPs 6
2.1.2. Biological Activities of CAPs 8
2.1.3. Proposed Mechanisms of CAPs Action 8
2.1.4. Tryptophan-Rich Antimicrobial Peptide Indolicidin 13
2.1.4.1. Characteristics of Indolicidin 13
2.1.4.2. Lower Cytotoxicity Indolicidin-Analogues Design 14
2.2. Fluorescence Analysis of Peptide-Membrane Interaction 16
2.3. Molecular Dynamics Simulation 18
2.3.1. Background of MD Simulation 18
2.3.2. MD Simulation of Peptide-Membrane Interaction 24
CHAPTER 3. MATERIALS AND METHODS 26
3.1. MD Simulation Methods 26
3.1.1. System Building 26
3.1.2. Force Field and Simulation Setup 27
3.1.3. Simulation Analysis 28
3.1.3.1. Membrane Ordering 28
3.1.3.2. Minimum Salt Bridge Distance 28
3.2. Experimental Methods 29
3.2.1. Chemical Compounds and Biomolecules 29
3.2.2. Measurements of the Bioactivities of IL and Its Analogues 29
3.2.3. Preparation of SUVs 30
3.2.4. Fluorescence Spectra Measurements 31
3.2.5. AAm Quenching of Peptides in PBS Buffer 31
3.2.6. Dual-functional Fluorescence Quenching Assays 32
3.2.7. CD Measurements 32
3.2.8. Peptide-SUVs Equilibrium Dialysis Measurements 33
3.2.9. Quantification of Intrinsic Fluorescence of Peptides in SUVs 33
3.2.10. Dispersion Index of Peptides in Aqueous Solution 34
3.2.11. Dispersion Index of Peptides in SUVs 34
3.2.12. Dispersion Index and Depth Index of Peptides in SUVs 34
CHAPTER 4. MD SIMULATIONS FOR IL-ANALOGUES DESIGN 36
4.1. Equilibrium of Two Model Lipid Bilayers 36
4.2. IL-Model Membranes Interaction 37
4.2.1. IL-POPC Lipid Bilayer Association 37
4.2.2. IL–Mixed POPG/POPC Lipid Bilayer Association. 39
4.2.3. Definitions of Adsorption and Stable Insertion Stages. 40
4.2.4. IL-Mediated Lipid Bilayer Disordering. 41
4.2.5. Critical Amino Acids for the Disordering of Lipid Bilayer. 44
4.4. Antimicrobial and Hemolytic Activities of Designed Peptides. 50
4.5. MD simulation of IL-analogues with Model Lipid Bilayer 54
CHAPTER 5. ACTION OF CAPS-MEMBRANE ASSOCIATION 56
5.1. Aggregation of IL-Analogues in Aqueous Solution 56
5.1.1. Determination of aggregation of IL-Analogues 57
5.1.2. Driving Force of Peptide Aggregation 59
5.2. IL-analogues and Model Membranes Interactions 60
5.2.1. Amounts of IL-analogues Adsorption to Model Membranes 61
5.2.2. Degree of Peptide Dispersion within the Model Membranes 62
5.2.3. Insertion Depth of IL-Analogues in Model Membrane 63
5.3. Implications on Cationic Antimicrobial Peptide Design 64
CHAPTER 6. CONCLUSIONS 67
FIGURES 70
TABLES 94
REFERENCES 97
APPENDIX-PUBLICATION LISTS 112

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指導教授

阮若屈、蔡惠旭
(Ruoh-chyu Ruaan、Hui-Hsu Gavin Tsai)

審核日期

2010-7-29

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