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Conformational Transition Mechanisms of Flexible Proteins CONFORMATIONAL TRANSITION MECHANISMS OF FLEXIBLE PROTEINS A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Swarnendu Tripathi December 2010 Dissertation written by Swarnendu Tripathi B.Sc., ST. Xavier’s College, University of Calcutta, 2000 M.Sc., University of Pune, 2002 M.Tech., Indian Institute of Technology Bombay, 2004 M.A., Kent State University, 2006 Ph.D., Kent State University, 2010 Approved by Dr. John J. Portman , Chair, Doctoral Dissertation Committee Dr. Robin L. B. Selinger , Members, Doctoral Dissertation Committee Dr. Almut Schroeder Dr. Hamza Balci Dr. Arne Gericke Accepted by Dr. James T. Gleeson , Chair, Department of Physics Dr. Timothy Moerland , Dean, College of Arts and Sciences ii TABLE OF CONTENTS LISTOFFIGURES ................................ viii ACKNOWLEDGMENTS . xxviii Dedication...................................... xxxi 1 INTRODUCTION ............................... 1 1.1 Overview.................................. 1 1.2 ProteinStructure ............................. 2 1.3 Theory of Protein Folding from Energy Landscape Perspective.... 5 1.3.1 Thefunnellandscape....................... 6 1.4 Remodeled Energy Landscapes of Functional Transitions in Proteins . 7 1.5 ProteinMotions.............................. 8 1.5.1 Fast timescale (small amplitude) motions . .. 10 1.5.2 Slow timescale (large amplitude) motions . .. 11 1.6 Proteins Studied in this Dissertation . ... 13 1.6.1 Calmodulin ............................ 13 1.6.2 NitrogenregulatoryproteinC(NtrC) . 18 1.7 OrganizationofDissertation . 21 iii 2 BACKGROUND INFORMATION ON COARSE-GRAINED MODELING OF PROTEIN CONFORMATIONAL TRANSITIONS . 24 2.1 Introduction................................ 24 2.2 Elastic Network Models for a Single Minimum . .. 26 2.3 Elastic Network Models for Two Minima . 30 2.4 Coarse-grained MD Models for Conformational Transitions...... 34 2.4.1 Takada-Onuchic-Wolynes model . 34 2.4.2 Best-Hummermodel . .. .. 36 3 MODELANDMETHODS........................... 39 3.1 Variational Model of Conformational Transitions . ....... 40 3.1.1 Hamiltonianoftheproteinsystem. 40 3.1.2 Reference Hamiltonian for two known structures . ... 42 3.1.3 Approximating the free energy surface . 46 3.1.4 Modeling the energy of conformational transition . .... 49 3.1.5 Analysis of conformational transition route . .... 50 3.1.6 Orderparameters......................... 51 3.2 VariationalModelofFolding. 54 3.2.1 Analysisoffoldingroute . 55 3.2.2 Orderparameters......................... 57 3.3 ModelParameters............................. 58 iv 4 THE OPEN/CLOSED CONFORMATIONAL TRANSITION OF THE N- TERMINALDOMAINOFCALMODULIN . 60 4.1 Introduction................................ 60 4.2 Methods.................................. 64 4.3 Conformational Flexibility and Calcium Binding . ...... 65 4.3.1 Bindingloops ........................... 66 4.3.2 Helices B and C and the B/C linker . 69 4.4 Conformational Transition Mechanism . .. 70 4.4.1 BindingloopsIandII ...................... 72 4.4.2 Methionineresidues. 75 4.5 Conformational Transition Rate and Order Parameters . ...... 77 4.6 Conclusion................................. 79 5 CONFORMATIONAL TRANSITION MECHANISMS OF THE EF-HANDS OFCALMODULIN............................... 81 5.1 Introduction................................ 81 5.2 Methods.................................. 87 5.3 N-Terminal and C-Terminal Domains of CaM . 88 5.3.1 Conformational flexibility of the CaM domains . .. 88 5.3.2 Cracking in the conformational transition of cCaM . ... 90 5.3.3 Open/closed transition mechanism of the CaM domains . ... 92 5.4 CaM2/3Fragment ............................ 93 v 5.4.1 Conformational flexibility and cracking of CaM2/3 . ... 93 5.4.2 Conformational transition mechanism of CaM2/3 . .. 97 5.5 Discussion................................. 97 6 INTERPLAY AMONG TOPOLOGY, PLASTICITY AND ENERGETICS IN THE FUNCTIONAL TRANSITIONS OF THE CALMODULIN DO- MAINS ..................................... 102 6.1 Introduction................................ 102 6.2 StrainEnergyAnalysis . 104 6.3 Analysis of Conformational Flexibility and Cracking . ........ 110 6.4 Relationship between Free Energy Barrier and Inherent Flexibility . 115 6.5 Conclusions ................................ 117 7 CONFORMATIONAL TRANSITION AND FOLDING MECHANISMS OF THE N-TERMINAL RECEIVER DOMAIN OF PROTEIN NTRC . 118 7.1 Introduction................................ 118 7.2 Methods.................................. 121 7.3 Folding Mechanism of NtrCr ....................... 122 7.3.1 Folding of the inactive-NtrCr .................. 122 7.3.2 Folding of the active-NtrCr .................... 125 7.4 Conformational Transition of NtrCr ................... 127 7.4.1 Inactive to active state transition routes of NtrCr ....... 127 7.4.2 Conformational flexibility of NtrCr ............... 130 vi 7.4.3 Inactive to active transition mechanism of NtrCr ........ 132 7.4.4 Strain energy analysis of inactive NtrCr ............. 135 7.4.5 Comparison with experimentally predicted transition mechanism139 7.5 Discussion ................................. 142 7.6 Conclusions ................................ 143 8 CONCLUSIONS ................................ 145 9 APPENDIX................................... 148 9.1 The Stiff Chain Model for Polypeptide Backbone . 148 9.2 Variational Free Energy Approximation . ... 150 BIBLIOGRAPHY ................................. 151 vii LIST OF FIGURES 1.1 Schematic illustration of different levels of protein structures. Primary structure is a chain of amino acid sequence (shown in three letter code) contains all the information needed to specify (a). Secondary structures such as α-helix and β-sheet are formed from the regular repeating pat- terns of backbone hydrogen bonds (b). The way secondary structural elements pack together to form the overall three-dimensional fold of the protein is tertiary structure (P13 protein) (c). The relative arrange- ment of two or more individual polypeptide chains is called quaternary structure (hemoglobin) (d). Adapted from wikimedia [1]. .... 4 1.2 The funnel-shape free energy landscape for protein folding. Folding occurs through the progressive organization of ensembles of structures [example is src-SH3 domain (left)] on a free energy landscape. Confor- mational entropy loss during folding is compensated by the free energy gained as more native interactions are formed. Adapted from Brooks et al. [2]. ................................. 7 viii 1.3 Remodeled energy landscape to accommodate protein functional dy- namics. (A) Schematic illustration of the free energy landscape (red: higher energy, blue: lower energy). The box region encloses conforma- tional states that are energetically available for interconversion under physiological conditions. (B) A signal such as, ligand can remodel the energy landscape by narrowing down the number of ensemble states in a single energy well through structural rigidification of the average conformation. (C) Alternatively, a protein may already exist in equi- librium between conformationally distinct states and a ligand can alter the relative energies or population of the states, resulting in redistri- bution of their occupancies. (D) A slight variation on (C) may occur if the population of the higher-energy state shifts toward a ligand- induced conformation in the absence of ligand. Adapted from Smock andGierasch [3]. ............................ 9 1.4 Types of protein motions in different timescale and the experimental methods to characterize fluctuations on each timescale. Adapted from Henzler-WildermanandKern [4]. 11 ix 1.5 Function of calcium-binding EF-hand protein calmodulin. (a) Calcium binding occurs to the EF-hand subdomains of calmodulin, which favors binding to a target molecule such as myosin light chain kinase. Binding of the target to one site on calmodulin enhances binding affinity to a second binding site [5]. Adapted from Smock and Gierasch [3]. (b) The EF-hand helix-loop-helix motif. The index finger represents helix- E (shown in yellow), thumb is helix-F (shown in blue), and, rest of the fingers are binding loop (shown in red and calcium ion in green). AdaptedfromRef.[6]. .......................... 14 1.6 Calcium induced conformational change in calmodulin. The EF-hands of the two domains of unbound-calmodulin [PDB: 1cfd, (left)] undergo large structural rearrangement upon calcium binding and exposes hy- drophobic surface on each domain to bind target proteins. The cal- cium ions are shown in white spheres in bound-calmodulin [PDB: 1cll, (right)]. These three-dimensional protein figures and others in this dissertation are made using Visual Molecular Dynamics (VMD) pro- gram[7]. ................................. 17 x 1.7 The transcriptional activation mechanism by NtrC. (a) The glnA gene is transcribed by the σ54-containing polymerase which alone cannot initiate transcription. The unphosphorylated NtrC dimers can bind only one site at the enhancer, still insufficient to stimulate transcrip- tion. (b) The phosphorylated NtrC dimers can bind both sites of the enhancer. (c) Their binding induces DNA looping. Contact between the activator and the polymerase stabilizes the interaction between the polymerase and DNA, thereby initiating transcription. Adapted from web-book[8]. ............................... 19 1.8 Phosphorylation induces large conformational change in the N-terminal receiver domain of NtrC at the active site Asp54 (near the C-terminal end of β3). The unphosphorylated
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