中文摘要
果蠅多巴胺乙醯基轉移酶(dopamine N-acetyltransferase, Dat) 屬於苯烷基胺乙醯轉移酶的一種 (arylalkylamine N-acetyltransferase, AANAT; EC 2.3.1.87)，會催化褪黑激素 (melatonin) 前驅物的生成，近期以來，我們實驗室已經解出多巴胺乙醯基轉移酶晶體 (apo form) 和多巴胺乙醯基轉移酶晶體/乙醯輔酶A複合晶體 (complex form) 之蛋白質結構，並分析了多巴胺乙醯基轉移酶與基質間結合的動力學機制，而在這個研究中，我們成功解出解析度高達1.20 Å的多巴胺乙醯基轉移酶的三元複合體，我們根據此結構發現三個芳香族殘基顯示在活性位置疏水性基質接合空腔的附近，可能對於基質選擇的專一性具有很大的影響。因此，多巴胺乙醯基轉移酶中的三個殘基F43、Y64 以及 F114 分別被突變為色胺酸。酵素動力學證實，F43W明顯降低多巴胺乙醯基轉移酶對基質的結合與活性，說明了這個殘基在酵素活性以及基質接合扮演重要角色；相反的，F114W殘基則是不影響酵素活性以及基質選擇性；然而，利用等溫滴定微量測焓儀（ITC）及酵素動力學的聯合證實，Y64W突變體具有對基質的廣效性，不僅提高了酵素活性，也增加了對吲哚烷基胺的選擇性，這些結果證實，Y64殘基可能調控多巴胺乙醯基轉移酶在酵素和基質之間的pi-pi作用力。我們的研究提供了一個三元複合體結構的基礎，可能有助於了解果蠅AANAT的酵素活性以及殘基與基質選擇性的關係。

Abstract
Drosophila melanogaster dopamine N-acetyltransferase (Dat, EC 2.3.1.87) is an arylalkylamine N-acetyltransferase (AANAT) which catalyzes the synthesis of the hormonal precursor (melatonin). The structures of Dat both in the apo form and in complexed with acetyl coenzyme A and the catalytic mechanism have been solved in our laboratory. In this study, we report the crystal structure of Dat ternary complex with coenzyme A and serotonin at 1.20 Å resolution. According to our structure, we proposed that three aromatic residues (F43, Y64, and F114) in a hydrophobic substrate-binding pocket of Dat may play key roles in substrate specificity. These three residues F43, Y64 and F114 were individually replaced with tryptophan to estimate the effect of an indole ring in the substrate selectivity. Enzyme kinetic studies demonstrated that mutant F43W apparently decreased the substrate binding and the activity of wild type, indicating this residue is critical for enzyme activity. On the contrary, F114W demonstrated no relationship with substrate selectivity or substrate binding. According to the previous study, wild type has substrate specificity with phenylalkylamine. However, the kinetic results combined with ITC data showed that the Y64W had a broad spectrum substrate selectivity slightly enhanced the enzyme activity toward indoalkylamine. The result indicated that residue Y64 may modulate the pi-pi interaction between Dat and substrates. Our study contributes a ternary complex structural that may help to understand enzyme activity and the substrate binding selectivity in Drosophila AANAT.

Contents
Abstract in Chinese i
Abstract ii
Acknowledgement iii
Contents v
List of Tables and Figures vii
Abbreviations x
Keywords xi
Chapter 1. Introduction 1
1.1 Overview of Dopamine N-acetyltransferase (Dat) from Drosophila melanogaster 1
1.2 Physiological and Pharmacological Functions of Substrates for AANAT 3
1.3 Dat: A member of GCN5-related N-acetyltransferase (GNAT) superfamily 4
1.4 Motivation of the Study 5
Chapter 2. Experimental Method 6
2.1 Protein Expression and Purification 6
2.2 Identification of Enzyme Purity 8
2.3 Crystallization and Data Collection 10
2.4 Data Processing and Construction of Density Map 11
2.5 Circular Dichroism Spectroscopy 12
2.6 DTNB-based Enzyme Activity Measurements 13
2.7 Isothermal Titration Calorimetry 14
Chapter 3. Result and Discussion 15
3.1 Crystal Structure of the Dat21–230/CoA/N-acetyl-serotonin Complex 15
3.2 Superimposition of Binary and Ternary Complex of Dat 18
3.3 Characterization of Dat 20
3.4 Substrate Selectivity of Dat 20
3.5 Isothermal Titration Calorimetry Binding Assay of Dat/CoA with substrate 23
3.6 Mutation at Y64 Can Change Substrate Preference to Broad Spectrum Substrate Activity 25
Chapter 4. Conclusions 28
Chapter 5. Future works 29
References 30
Appendix 82

Reference
Alex C. Keene, S. W. (2007). Drosophila olfactory memory: single genes to complex neural circuits. Nature Reviews Neuroscience 8, 341-354.
Amherd, R., Hintermann, E., Walz, D., Affolter, M., and Meyer, U. A. (2000). Purification, cloning, and characterization of a second arylalkylamine N-acetyltransferase from Drosophila melanogaster. DNA and cell biology 19, 697-705.
Bailey, S. (1993). The CCP4 suite: programs for protein crystallography: Daresbury Laboratory).
Bansal, S. An Introduction to Mass Spectrometry Based Proteomics Prepared by Drs Andrew Kicman, Mark Parkin and.
Barducci, A., Chelli, R., Procacci, P., and Schettino, V. (2005). Misfolding pathways of the prion protein probed by molecular dynamics simulations. Biophysical journal 88, 1334-1343.
Blenau, W., and Baumann, A. (2001). Molecular and pharmacological properties of insect biogenic amine receptors: Lessons from Drosophila melanogaster and Apis mellifera. Archives of Insect Biochemistry and Physiology 48, 13-38.
Blond-Elguindi, S., Cwirla, S. E., Dower, W. J., Lipshutz, R. J., Sprang, S. R., Sambrook, J. F., and Gething, M.-J. H. (1993). Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 75, 717-728.
Bogyo, M., Shin, S., McMaster, J. S., and Ploegh, H. L. (1998). Substrate binding and sequence preference of the proteasome revealed by active-site-directed affinity probes. Chemistry & biology 5, 307-320.
Briinger, A. T. (1992). Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 355, 472-475.
Britta Haenisch, H. B. (2011). Depression and antidepressants: Insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Pharmacology & therapeutics 129, 352–368.
Bruno P. Guiard, M. E. M., Zul Merali and Pierre Blier (2008). Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. The international journal of neuropharmacologie 11, 625-639.
Brzezinski, A. (1997). Mechanisms of Disease Melatonin in Humans. The New England Journal of Medicine 336, 186-195.
Burley, S., and Petsko, G. (1985). Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science 229, 23-28.
Burley, S., and Petsko, G. (1986). Amino-aromatic interactions in proteins. FEBS letters 203, 139-143.
Cavasotto, C. N., and Abagyan, R. A. (2004). Protein flexibility in ligand docking and virtual screening to protein kinases. Journal of molecular biology 337, 209-225.
Chakrabartty, A., Kortemme, T., Padmanabhan, S., and Baldwin, R. L. (1993). Aromatic side-chain contribution to far-ultraviolet circular dichroism of helical peptides and its effect on measurement of helix propensities. Biochemistry 32, 5560-5565.
Cheng, K.-C. (2013). Structural and functional studies of dopamine N-acetyltransferase from Drosophila melanogaster. In, (National Tsing Hua University).
Cheng, K. C., Liao, J. N., and Lyu, P. C. (2012a). Crystal structure of the dopamine N-acetyltransferase-acetyl-CoA complex provides insights into the catalytic mechanism. The Biochemical journal 446, 395-404.
Cheng, K. C., Liao, J. N., and Lyu, P. C. (2012b). Crystal structure of the dopamine N-acetyltransferase–acetyl-CoA complex provides insights into the catalytic mechanism. Biochemical Journal 446, 395-404.
Choudhary, M., Sachs, N., Uluer, A., Glennon, R., Westkaemper, R., and Roth, B. (1995). Differential ergoline and ergopeptine binding to 5-hydroxytryptamine2A receptors: ergolines require an aromatic residue at position 340 for high affinity binding. Molecular pharmacology 47, 450-457.
Colquhoun, D. (1998). Binding, gating, affinity and efficacy: The interpretation of structure‐activity relationships for agonists and of the effects of mutating receptors. British journal of pharmacology 125, 923-947.
Connors, K. A. (1987). Binding constants: the measurement of molecular complex stability: Wiley New York).
Cooke, M. S., Evans, M. D., Dizdaroglu, M., and Lunec, J. (2003). Oxidative DNA damage: mechanisms, mutation, and disease. The FASEB Journal 17, 1195-1214.
Coon, S. L., Bégay, V., Deurloo, D., Falcón, J., and Klein, D. C. (1999). Two arylalkylamine N-acetyltransferase genes mediate melatonin synthesis in fish. JOURNAL OF BIOLOGICAL CHEMISTRY 274, 9076-9082.
Corpet, F. (1988). Multiple sequence alignment with hierarchical clustering. Nucleic acids research 16, 10881-10890.
Creese, I., Burt, D. R., and Snyder, S. H. (1976). Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481-483.
Damm, K. L., and Carlson, H. A. (2006). Gaussian-weighted RMSD superposition of proteins: a structural comparison for flexible proteins and predicted protein structures. Biophysical journal 90, 4558-4573.
David C. Klein, S. L. C., Patrick H. Roseboom, J.L.Weller (1997). The Melatonin Rhythm-generating Enzyme: Molecular Regulation of Serotonin N-acetyltransferase in the Pineal Gland. Hormone research 52, 307-358.
De Angelis, J., Gastel, J., Klein, D. C., and Cole, P. A. (1998). Kinetic analysis of the catalytic mechanism of serotonin N-acetyltransferase (EC 2.3. 1.87). JOURNAL OF BIOLOGICAL CHEMISTRY 273, 3045-3050.
DeLano, W. L. (2002). The PyMOL molecular graphics system.
Dougherty, D. A. (1996). Cation-π interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science 271, 163-168.
Dr. Richard J. Wurtman, J. J. W. (1995). Brain Serotonin, Carbohydrate-Craving, Obesity and Depression. Obesity 3, 477S–480S.
E. Beutler, O. D., BM Kelly (1963). Improved method for determination of blood glutathione. j Lab Clin Med 61, 882-890.
E.K. Perry, R. H. P., J.M. Candy, A.F. Fairbairn, G. Blessed, D.J. Dick, B.E. Tomlinson (1984). Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer's disease: Comparisons with Parkinson's disease. Neuroscience 51, 353-357.
Ehab M. Khalil, J. D. A., Makoto Ishii, and Philip A. Cole (1999). Mechanism-based inhibition of the melatonin rhythm enzyme: Pharmacologic exploitation of active site functional plasticity. PNAS 96, 12418–12423.
Eisenthal, R. (1974). The direct linear plot. A new graphical procedure for estimating enzyme kinetic parameters. Biochem J 139, 715-720.
Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallographica Section D: Biological Crystallography 60, 2126-2132.
Fersht, A. (1999). Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding: Macmillan).
Fred Dyda, D. C. K., and, and Hickman, A. B. (2000). GCN5-RELATED N-ACETYLTRANSFERASES: A Structural Overview. Annu Rev Biophys Biomol Struct 29, 81–103.
G. A. Smythe, L. L. (1973). Growth Hormone Regulation by Melatonin and Serotonin. Nature 244, 230 - 231.
Gogstad, G. O., and Krutnes, M.-B. (1982). Measurement of protein in cell suspensions using the Commassie brilliant blue dye-binding assay. Analytical Biochemistry 126, 355-359.
Golden RN, G. J., Corrigan MH, Ekstrom RD, Knight BT, Garbutt JC. (1991). Serotonin, suicide, and aggression: clinical studies. J Clin Psychiatry 52, 61-70.
Green, A. R. (1985). Neuropharmacology of serotonin: Oxford University Press Oxford).
Guex, N., and Peitsch, M. C. (1997). SWISS‐MODEL and the Swiss‐Pdb Viewer: an environment for comparative protein modeling. electrophoresis 18, 2714-2723.
Hall, T. A. (1999). BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Paper presented at: Nucleic acids symposium series.
Harel, M., Schalk, I., Ehret-Sabatier, L., Bouet, F., Goeldner, M., Hirth, C., Axelsen, P., Silman, I., and Sussman, J. (1993). Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proceedings of the National Academy of Sciences 90, 9031-9035.
Hickman, A. B., Namboodiri, M., Klein, D. C., and Dyda, F. (1999). The structural basis of ordered substrate binding by serotonin N-acetyltransferase: enzyme complex at 1.8 Å resolution with a bisubstrate analog. Cell 97, 361-369.
Hsiao, Y.-S., Jogl, G., and Tong, L. (2006). Crystal structures of murine carnitine acetyltransferase in ternary complexes with its substrates. JOURNAL OF BIOLOGICAL CHEMISTRY 281, 28480-28487.
Hunter, C. A., and Sanders, J. K. (1990). The nature of. pi.-. pi. interactions. Journal of the American Chemical Society 112, 5525-5534.
Ivanovskaya, M., Kotsikau, D., Faglia, G., and Nelli, P. (2003). Influence of chemical composition and structural factors of Fe2O3/In2O3 sensors on their selectivity and sensitivity to ethanol.
Johnson, W. C. (1990). Protein secondary structure and circular dichroism: a practical guide. Proteins: Structure, Function, and Bioinformatics 7, 205-214.
Jones, T. A., Zou, J.-Y., Cowan, S. t., and Kjeldgaard, M. (1991). Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallographica Section A: Foundations of Crystallography 47, 110-119.
Jr., W. C. J. (1990). Protein secondary structure and circular dichroism: A practical guide. Proteins, 205-214.
Khalil, E. M., De Angelis, J., and Cole, P. A. (1998). Indoleamine analogs as probes of the substrate selectivity and catalytic mechanism of serotonin N-acetyltransferase. JOURNAL OF BIOLOGICAL CHEMISTRY 273, 30321-30327.
Kicman, A. T., Parkin, M. C., and Iles, R. K. (2007). An introduction to mass spectrometry based proteomics--detection and characterization of gonadotropins and related molecules. Molecular and cellular endocrinology 260, 212-227.
Klein, D. C. (2007). Arylalkylamine N-Acetyltransferase:“the Timezyme”. JOURNAL OF BIOLOGICAL CHEMISTRY 282, 4233–4237.
Kou Takahashi, A. S., Misa Yamada, Yoshiaki Maruyama, Noritaka Hirose, Junzo Kamei, Mitsuhiko Yamada (2008). Gene Expression Profiling Reveals Complex Changes in the Olfactory Bulbectomy Model of Depression After Chronic Treatment With Antidepressants. Pharmacological Sciences 208, 320-334.
Krauss, N., Hinrichs, W., Witt, I., Fromme, P., Pritzkow, W., Dauter, Z., Betzel, C., Wilson, K. S., Witt, H. T., and Saenger, W. (1993). Three-dimensional structure of system I of photosynthesis at 6 Å resolution. Nature 361, 326-331.
Krissinel, E., and Henrick, K. (2004). Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallographica Section D: Biological Crystallography 60, 2256-2268.
L. Finocchiaro, J. C., J. M. Launay, and J. M. Jallon (1988). Melatonin Biosynthesis in Drosophila: Its Nature and Its Effects. J Neurochemistry 50, 382-387.
Limbach, L. K., Wick, P., Manser, P., Grass, R. N., Bruinink, A., and Stark, W. J. (2007). Exposure of engineered nanoparticles to human lung epithelial cells: influence of chemical composition and catalytic activity on oxidative stress. Environmental Science & Technology 41, 4158-4163.
Lineweaver, H., and Burk, D. (1934). The determination of enzyme dissociation constants. Journal of the American Chemical Society 56, 658-666.
Maina, C. V., Riggs, P. D., Grandea III, A. G., Slatko, B. E., Moran, L. S., Tagliamonte, J. A., McReynolds, L. A., and Chu, d. G. (1988). An< i> Escherichia coli vector to express and purify foreign proteins by fusion to and separation from maltose-binding protein. Gene 74, 365-373.
McMillan, W. O., Monteiro, A., and Kapan, D. D. (2002). Development and evolution on the wing. Trends in Ecology & Evolution 17, 125-133.
Meyer, E. A., Castellano, R. K., and Diederich, F. (2003). Interactions with aromatic rings in chemical and biological recognition. Angewandte Chemie International Edition 42, 1210-1250.
Morris, A. L., MacArthur, M. W., Hutchinson, E. G., and Thornton, J. M. (1992). Stereochemical quality of protein structure coordinates. Proteins: Structure, Function, and Bioinformatics 12, 345-364.
O'Hayre, R. P., Cha, S.-W., Colella, W., and Prinz, F. B. (2006). Fuel cell fundamentals: John Wiley & Sons New York).
Osanai-Futahashi, M., Ohde, T., Hirata, J., Uchino, K., Futahashi, R., Tamura, T., Niimi, T., and Sezutsu, H. (2012). A visible dominant marker for insect transgenesis. Nat Commun 3, 1295.
Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data. Methods enzymol 276, 307-326.
Otwinowski, Z., and Minor, W. (2001). Denzo and Scalepack. Crystallography of Biological Macromolecules, 226-235.
Pérez-Jordá, J., and Becke, A. D. (1995). A density-functional study of van der Waals forces: rare gas diatomics. Chemical physics letters 233, 134-137.
Patrick Emery, W. V. S., Maki Kaneko,, and Jeffrey C. Hall, a. M. R. (1988). CRY, a Drosophila Clock and Light-Regulated Cryptochrome, Is a Major Contributor to Circadian Rhythm Resetting and Photosensitivity. Cell 669–679, 95.
Peroutka, J. (1980). Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency. Am J Psychiatry 137, 1518-1522.
Peter Karlson, C. E. S. (1962). N-acetyl-dopamine as sclerization agent of the insect cuticle. Physiolog Chem 195, 183-184.
Pierre Blier, C. d. M. (1999). Serotonin and Drug-Induced Therapeutic Responses in Major Depression, Obsessive–Compulsive and Panic Disorders. Neuropsychopharmacology 21, 91S–98S.
Pluskal, M. G. (2000). Microscale sample preparation. Nature biotechnology 18, 104-105.
Raghunand, N., Martı́nez–Zaguilán, R., Wright, S. H., and Gillies, R. J. (1999). pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs. Biochemical pharmacology 57, 1047-1058.
Richardson, J. S., Arendall Iii, W. B., and Richardson, D. C. (2003). New Tools and Data for Improving Structures, Using All-Atom Contacts. In Methods in Enzymology, Charles W. Carter, Jr., and M.S. Robert, eds. (Academic Press), pp. 385-412.
Rose, G. D., Geselowitz, A. R., Lesser, G. J., Lee, R. H., and Zehfus, M. H. (1985). Hydrophobicity of amino acid residues in globular proteins. Science 229, 834-838.
Satyanarayana, S., Dabrowiak, J. C., and Chaires, J. B. (1993). Tris (phenanthroline) ruthenium (II) enantiomer interactions with DNA: mode and specificity of binding. Biochemistry 32, 2573-2584.
Segel, I. H. (1993). Enzyme kinetics: Wiley New York).
Sharp, K. (2001). Entropy—enthalpy compensation: Fact or artifact? Protein Science 10, 661-667.
Simmerling, C., Strockbine, B., and Roitberg, A. E. (2002). All-atom structure prediction and folding simulations of a stable protein. Journal of the American Chemical Society 124, 11258-11259.
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J., and Klenk, D. C. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry 150, 76-85.
Steitz, T. A., Fletterick, R. J., and Hwang, K. J. (1973). Structure of yeast hexokinase: II. A 6 Å resolution electron density map showing molecular shape and heterologous interaction of subunits. Journal of molecular biology 78, 551-561.
Steven L. Coon, P. H. R., Ruben Baler, Joan L. Weller, M. A. A.Namboodiri, Eugene V. Koonin, David C. KleinSource (1995). Pineal Serotonin N-Acetyltransferase: Expression Cloning and Molecular Analysis. Science 270, 1681-1683.
Sylvia Aust, T. T., Susanne Humpeler, WalterJa¨ger,, Martin Klimpfinger, G. T., Peter Obrist5, W. M., Cem, E. P. a., and Ekmekcioglu (2004). The melatonin receptor subtype MT1 is expressed in human gallbladder epithelia. J Pineal Res 36, 43-48.
Tama, F., and Sanejouand, Y.-H. (2001). Conformational change of proteins arising from normal mode calculations. Protein Engineering 14, 1-6.
Teague, S. J. (2003). Implications of protein flexibility for drug discovery. Nature Reviews Drug Discovery 2, 527-541.
Thompson, J. D., Gibson, T. J., Plewniak, F., Jeanmougin, F., and Higgins, D. G. (1997). The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic acids research 25, 4876-4882.
Van Oss, C., Absolom, D., and Neumann, A. (1979). Repulsive van der Waals forces. II. Mechanism of hydrophobic chromatography. Separation Science and Technology 14, 305-317.
Vetting, M. W., S de Carvalho, L. P., Yu, M., Hegde, S. S., Magnet, S., Roderick, S. L., and Blanchard, J. S. (2005a). Structure and functions of the GNAT superfamily of acetyltransferases. Archives of Biochemistry and Biophysics 433, 212-226.
Vetting, M. W., S. de Carvalho, L. P., Yu, M., Hegde, S. S., Magnet, S., Roderick, S. L., and Blanchard, J. S. (2005b). Structure and functions of the GNAT superfamily of acetyltransferases. Archives of Biochemistry and Biophysics 433, 212-226.
Waddell, S., Armstrong, J. D., Kitamoto, T., Kaiser, K., and Quinn, W. G. (2000). The amnesiac Gene Product Is Expressed in Two Neurons in the Drosophila Brain that Are Critical for Memory. Cell 103, 805-813.
Watson, W. T., Minogue, T. D., Val, D. L., von Bodman, S. B., and Churchill, M. E. (2002). Structural basis and specificity of acyl-homoserine lactone signal production in bacterial quorum sensing. Molecular cell 9, 685-694.
Wessolowski, A., Bienert, M., and Dathe, M. (2004). Antimicrobial activity of arginine‐and tryptophan‐rich hexapeptides: the effects of aromatic clusters, d‐amino acid substitution and cyclization. The Journal of peptide research 64, 159-169.
Wilker, E. W., Grant, R. A., Artim, S. C., and Yaffe, M. B. (2005). A structural basis for 14-3-3σ functional specificity. JOURNAL OF BIOLOGICAL CHEMISTRY 280, 18891-18898.
Wiseman, T., Williston, S., Brandts, J. F., and Lin, L.-N. (1989). Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Analytical Biochemistry 179, 131-137.
Woody, R. W. (1995). Circular dichroism. In Methods in Enzymology, S. Kenneth, ed. (Academic Press), pp. 34-71.
Wurtman, R. J., Wurtman, J. J., Regan, M. M., McDermott, J. M., Tsay, R. H., and Breu, J. J. (2003). Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios. The American journal of clinical nutrition 77, 128-132.
Ye, Y., and Godzik, A. (2003). Flexible structure alignment by chaining aligned fragment pairs allowing twists. Bioinformatics 19, ii246-ii255.
York, D., Darden, T., Pedersen, L., and Anderson, M. (1993). Molecular dynamics simulation of HIV-1 protease in a crystalline environment and in solution. Biochemistry 32, 1443-1453.
Young-Cho Kim, H.-G. L., and Kyung-An Han (2007). D1 Dopamine Receptor dDA1 Is Required in the Mushroom Body Neurons for Aversive and Appetitive Learning in Drosophila. The Journal of Neuroscience 27, 7640-7647.
Zilberman-Peled, B., Bransburg-Zabary, S., Klein, D. C., and Gothilf, Y. (2011). Molecular evolution of multiple arylalkylamine N-acetyltransferase (AANAT) in fish. Marine drugs 9, 906-921.