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Design of Molecular Mechanics Modeling Techniques for Exploring Molecular Recognition Using Cyclodextrins

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Design of Molecular Mechanics Modeling Techniques for Exploring Molecular Recognition Using Cyclodextrins University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2003 “Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins. Shannon Bradley Fox University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Chemistry Commons Recommended Citation Fox, Shannon Bradley, "“Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins.. " PhD diss., University of Tennessee, 2003. https://trace.tennessee.edu/utk_graddiss/2013 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Shannon Bradley Fox entitled "“Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins.." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. M. J. Sepaniak, Major Professor We have read this dissertation and recommend its acceptance: Elizabeth Howell, S. D. Gilman, Z. Xue Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) To the Graduate Council: I am submitting herewith a dissertation written by Shannon Bradley Fox entitled “Design of Molecular Mechanics Modeling Techniques For Exploring Molecular Recognition Using Cyclodextrins.” I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Chemistry. M. J. Sepaniak _______________________________ Major Professor We have read this dissertation and recommend its acceptance: Elizabeth Howell _______________________________ S. D. Gilman _______________________________ Z. Xue _______________________________ Accepted for the Council: Anne Mayhew _______________________________ Vice Provost and Dean of Graduate Studies (Original signatures are on file with official student records.) DESIGN OF MOLECULAR MECHANICS MODELING TECHNIQUES FOR EXPLORING MOLECULAR RECOGNITION USING CYCLODEXTRINS A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Shannon Fox December 2003 DEDICATION This dissertation is dedicated to my mother, Martha Fox and my father, Steve Fox and my sister, Elise Fox and Mohsena Purkaystha for their love, support, and encouragement. ii ACKNOWLEDGEMENTS There are many people who have helped me during my time in graduate school, and I don’t think I could have made it to the finish line without their assistance. First I would like to thank Dr. Mike Sepaniak for his continued patience, guidance, and support during my time as a graduate student. I would like to thank the many colleagues with whom I have had the privilege to work. Special thanks to fellow research group members Chris Tipple, Lance Riddle, Marco DeJesus, Mustafa Culha, and Jim Schaeper for their friendship during my time at UT. I would also like to express my appreciation to Dr. R. J. Hinde for his assistance with writing unix scripts for molecular modeling experiments, and to Dr. S. Douglass Gilman for his help and patience in maintaining the departmental website, and for being on my committee. Also thanks to Dr. Ben Xue and Dr. Elizabeth Howell for being committee members. Thanks to the many departmental support staff who have provided help and friendship over the years. Thanks to Bill Gurley and Johnny Jones for their tireless help with departmental network, and for teaching me many things during my time working with the Electronics Shop. Thanks to Trevor and Lenore Smith, John Edward, and Jeff Givens for their friendship, and for helping me enjoy my time here in Knoxville. Finally, I would like to thank my family for always being there for me. Their love, encouragement, and steadfast support has helped me more than they can know. iii ABSTRACT Molecular mechanics modeling techniques have been developed to study the behavior of cyclodextrins (CDs) in capillary electrophoresis (CE) separations. Using the commercial computational package, Sybyl, the mechanisms of molecular recognition between organic analytes and CDs are investigated. Cyclodextrin-modified capillary electrochromatography (CDCE) experiments were conducted to separate neutral derivitized naphthalene solutes using carboxymethyl- beta-cyclodextrin (CM-b-CD). Grid conformation-searching programs were developed to explore the interaction space between CD and solute and to calculate their interaction energies using molecular mechanics. The interaction energies correlated remarkably well with the separation behavior. It was found that extensive minimization (more than 3000 iterations) was required at each of the docking positions to achieve the best agreement between computational and experimental distribution coefficients (Kd). Molecular modeling techniques were also used to guide the development of a new charged cyclodextrin resolving agent, heptakis (6-O-carboxymethyl-2,3-dimethyl)-b- cyclodextrin (HDMCM-b-CD). Molecular computer aided design (MolCAD) analysis and docking techniques revealed that HDMCM-b-CD would be superior to commercially available CDs for forming inclusion complexes with the target naphthalene derivative analytes. Molecular modeling studies also showed that significant intermolecular CD- CD interactions can occur under certain conditions, explaining some anomalous experimental findings. Additionally, the grid conformation-searching modeling technique was applied to chiral CDCE separations of dansyl amino acids (AAs) to iv explain separation behavior and to investigate different CD-CD interactions. v TABLE OF CONTENTS CHAPTER PAGE 1. INTRODUCTION TO MOLECULAR RECOGNITION AND THE SUPRAMOLECULAR CHEMISTRY OF MACROCYCLIC COMPOUNDS ..................................................................................................... 1 Introduction and History .................................................................................... 1 Inclusion Complexes............................................................................................ 2 Crown Ethers and Cryptands ............................................................................. 4 Calixarenes........................................................................................................... 8 Cyclodextrins ...................................................................................................... 14 2. INTRODUCTION TO CAPILLARY ELECTROPHORESIS ..................... 20 Introduction and History .................................................................................. 20 Theory ................................................................................................................. 21 Electroosmotic Flow.............................................................................. 22 Observed Mobility.................................................................................. 25 Efficiency and Resolution ....................................................................... 27 Instrumentation.................................................................................................. 30 Buffer Additives................................................................................................. 32 Micellar Electrokinetic Chromatography.............................................. 32 Cyclodextrin Modified MEKC And Cyclodextrin Distribution Electrochromatography......................................................................... 36 Chiral Recognition.............................................................................................. 38 vi 3. INTRODUCTION TO COMPUTATIONAL MOLECULAR MODELING........................................................................................................ 40 Introduction......................................................................................................... 40 Molecular Mechanics.......................................................................................... 41 Force Fields.......................................................................................................... 41 Energy Calculation............................................................................................. 47 Conformation Searching .................................................................................... 48 Systematic Search .................................................................................. 48 Monte Carlo Searching.......................................................................... 49 Molecular Dynamics ........................................................................................... 50 Molecular Graphics ............................................................................................ 51 Minimization........................................................................................................ 52 4. DEVELOPMENT OF A
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