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Conformational Changes in Ligand Binding Processes Conformational Changes in Ligand Binding Processes Conformational Changes in Ligand Binding Processes Dissertation for the award of the degree Doctor rerum naturalium of the Georg-August-Universit¨atG¨ottingen within the doctoral program IMPRS-PBCS of the Georg-August University School of Science (GAUSS) Submitted by B´elaVoß from Hamburg G¨ottingen,2014 • Thesis Committee: { Prof. Dr. Helmut Grubm¨uller Department for Theoretical and Computational Biophysics Max-Planck-Institute for Biophysical Chemistry { Prof. Dr. J¨orgEnderlein Third Institute of Physics Faculty of Physics Georg-August-Universit¨atG¨ottingen { Prof. Dr. Marina Benatti Electron Spin Resonance Spectroscopy Group Max-Planck-Institute for Biophysical Chemistry • Examination Board: { Prof. Dr. Helmut Grubm¨uller(supervisor, reviewer) Department for Theoretical and Computational Biophysics Max-Planck-Institute for Biophysical Chemistry { Prof. Dr. J¨orgEnderlein (reviewer) Third Institute of Physics Faculty of Physics Georg-August-Universit¨atG¨ottingen { Prof. Dr. Marina Benatti Electron Spin Resonance Spectroscopy Group Max-Planck-Institute for Biophysical Chemistry { Prof. Dr. Sarah K¨oster CRC Research Group \Nanoscale Imaging of Cellular Dynamics" Faculty of Physics Georg-August-Universit¨atG¨ottingen { Dr. Thomas Burg Biological Micro- and Nanotechnology Group Max-Planck-Institute for Biophysical Chemistry { Prof. Dr. Markus M¨uller Institute for Theoretical Physics Faculty of Physics Georg-August-Universit¨atG¨ottingen Date of the disputation: 2015-01-30 iv Hiermit erkl¨areich, dass ich die vorliegende Arbeit selbstst¨andigverfasst und keine anderen als die angegebenen Quellen und Hilfsmittel verwendet habe. G¨ottingen,den 26.11.2014 B´elaVoß v Contents List of Abbreviations xi I. Opening 1 1. Introduction 3 2. Theoretical Background 5 2.1. Molecular Dynamics Simulations . .5 2.1.1. From Quantum Mechanics to Molecular Dynamics - Approx- imations for Force Field Based Molecular Dynamics . .5 2.1.2. Performing Molecular Dynamics Simulations . 10 2.2. Enhanced Sampling via Umbrella Sampling . 11 2.2.1. Potential of Mean Force . 11 2.2.2. Umbrella Sampling . 12 2.2.3. Weighted Histogram Analysis Method . 14 2.2.4. Hamiltonian Replica Exchange . 14 2.3. Principal Component Analysis . 15 2.4. Rate Estimation . 16 2.4.1. Rate Estimation if no Transitions Occur . 19 2.5. Diffusion Controlled Kinetics . 21 2.5.1. Rotational Restriction . 22 II. The Ligand Binding Mechanism of MloK1 25 3. Introduction 27 4. The Conformational Change in the CNBD 31 4.1. Introduction . 31 4.2. Theory . 33 4.2.1. Derivation of a Reaction Coordinate for the Conformational Change . 33 4.3. Methods . 35 4.3.1. Molecular Dynamics Simulations . 35 4.3.2. Data Analysis . 38 vii Contents 4.4. Results and Discussion . 39 4.4.1. Derivation of a Reaction Coordinate . 39 4.4.2. Free Energy Landscapes . 41 4.4.3. Rates of Conformational Changes . 46 4.4.4. Rates of Unbinding . 48 4.5. Conclusion . 52 5. The Binding of cAMP 55 5.1. Introduction . 55 5.2. Theory . 56 5.2.1. Substates and Pathways in a Ligand Binding Process . 56 5.2.2. Markov Model of Ligand Binding . 61 5.3. Methods . 62 5.3.1. Molecular Dynamics Simulations . 62 5.3.2. Data Analysis . 63 5.4. Results and Discussion . 66 5.4.1. Markov Model . 66 5.4.2. Protein Surface Attachment . 69 5.4.3. Three-State Model . 73 5.4.4. Binding Funnel . 75 5.5. Conclusion . 83 III. Long-range Allostery of CRM1 85 6. Introduction 87 6.1. Own Contribution . 90 7. Structural Basis for Cooperativity of CRM1 Export Complex Formation 93 8. Structural Determinants and Mechanism of Mammalian CRM1 Al- lostery 113 9. Conclusion 125 IV. Closing 129 10.Summary and Outlook 131 Appendix 133 Bibliography 133 viii Contents Acknowledgements 141 ix Acronyms cAMP cyclic adenosine monophosphate CNBD cyclic nucleotide binding domain CNG cyclic nucleotide gated COM centre of mass CRM1 chromosome region maintenance 1 MD molecular dynamics NES nuclear export signal NMR nuclear magnetic resonance NPC nuclear pore complex PCA principle component analysis PMF potential of mean force RanGTP the GTPase Ran in its GTP-bound form RMSD root mean square deviation SPN1 snurportin1 WHAM weighted histogram analysis method xi Part I. Opening 1 1. Introduction Ligand and protein-protein binding processes play a crucial role in biological pro- cesses. They are an essential part of the immune response; they are very often a first step in signalling processes, for example at G-protein coupled receptors; they are pre-requisites to ion channel activation, inactivation or modulation and they are an obvious part of cargo transport processes. An important subclass are processes where the protein adopts different confor- mations depending on the presence or absence of a binding partner. Since so many physiological processes are triggered, regulated or inhibited by ligand binding, many pharmaceutical drugs also work by binding to specific re- ceptors. Therefore, the understanding of these processes may also assist for the development of new pharmaceutical drugs. Consequently a lot of effort has been put into the investigation of such processes. Many experiments have been carried out to study the effects of ligand binding and the affinities of ligands to receptors. Furthermore, structural information on ligand binding processes has been obtained via x-ray crystallography and nuclear mag- netic resonance (NMR) spectroscopy. In those cases where the three-dimensional atomistic structure of the unbound and the bound complex has been solved, these structures represent the \end states" of the binding process. Much less is known on the pathways that connect these end states. Beside affinities, in most cases, the only available information are the rates between the unbound and bound state and vice versa, because it is usually difficult investi- gate the causal and temporal relation between ligand or protein binding and the conformational changes on an atomistic level. One way to fill the gap are all-atom molecular dynamics (MD) simulations, which are a powerful tool to investigate the molecular motions and conformational changes in proteins at atomistic resolution. Using the structural information about the end states they are principally very well suited to study the detailed mechanism of binding processes. In this thesis we want to address two major questions that are directly related to the pathway between the aforementioned end states: First: What is the sequential order of ligand binding and conformational change and what are the kinetics of the microscopic processes? Second: How does the binding lead to a conformational change and what are the functional consequences? To address these questions, we selected two different systems where the bound and unbound conformation are known and where binding plays a different func- tional role: The binding of the cyclic nucleotide cyclic adenosine monophosphate (cAMP) at the cyclic nucleotide binding domain (CNBD) of the potassium channel 3 1. Introduction MloK1 from the bacterium Mesorhizobium loti and the allosteric binding of pro- teins at the karyopherin, i.e. transport protein, chromosome region maintenance 1 (CRM1). In the former system, the CNBD of MloK1, binding at the binding domain leads to a conformational change in the binding domain that then influences the conduc- tivity of the ion channel. The systems is highly suited to address our first questions because additionally to structural information on the binding site there are also kinetic informations, i.e. the global on- and off-rates, available. Furthermore mu- tational studies have been carried out that already suggest that binding occurs before the conformational change. The availability of all these experimental data enables us to compare our findings with experimental measurements. In this work we focus solely on the binding domain for which we postulate a set of substates. We then develop and use a methodology to calculate the rates and free energy differences for transitions between these substates to understand the microscopic dynamics, determine the sequential order of binding and conforma- tional change and thereby classify the mechanism and derive estimates for effective on and off-rates which are then compared to experimentally measured rates. It will be fully introduced and discussed in detail in part II. In the latter system, CRM1, binding of a signal protein leads to a conformational change that changes the proteins affinity for cargo proteins. The exact cause of this allostery remained unclear though. Again it is not only the availability of structural information on the bound and unbound conformations that renders the system suitable for investigation, but also the information on the biological role, i.e. the transport of proteins from the nucleus into the cytoplasm, and the information that the allostery exists. Additionally, experiments have shown that a specific part of the protein is necessary for the allostery but were not able to fully explain this requirement. How the cooperative binding is achieved and what causes the conformational changes will be fully discussed in part III. First though we will introduce the basic theoretical background of the essentials techniques used in this work. 4 2. Theoretical Background In this chapter we will describe the essential established concepts that lay the foundation of our work. The method of MD simulations will be introduced, as well as some special simulation and analysis techniques. 2.1. Molecular Dynamics Simulations Biomolecules such as proteins
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