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Coarse-grained models of biomolecule dynamics and allostery

By Hedvika Toncrova


Recently, it has become increasingly accepted that thermal fluctuations take active part in functional tasks of biological molecules. We employ a set of coarse-grained models to investigate the mechanism of transmission of allosteric signal via spatial fluctuations. Our models are coarser than those in computational techniques established in molecular biology, but allow for both the identification of candidates for the essential physical structures and also the analytical determination of thermodynamic quantities that define ligand binding. The models are constructed for general classes of macromolecules and\ud are validated through parameterisation from experiments and atomistic simulations.\ud \ud In the first part of this thesis we investigate the “dynamic allostery” in dimeric proteins\ud composed of two identical subunits. We demonstrate that cooperative effects upon binding of two identical ligands can arise purely through modification of slow global\ud vibrational modes of the protein. We parameterise the model on a test case, the CAP homodimer. Finally, we explain the role of local, fast vibrations in the allosteric effect\ud and propose a general protocol for interpreting thermodynamic parameters of dynamically allosteric homodimers.\ud \ud The second part of this thesis considers allosteric effects in DNA, an example of nearly uniform elastic medium. The DNA is modeled as an elastic rod and substrate binding\ud as local increase of its bending and twisting rigidity. This results in altered structure of normal modes and leads to qualitatively different type of dynamic allostery compared to that of the discrete models previously employed to study allosteric effects in proteins. Dynamic allostery in DNA is found always to be negative, due to an anti-correlated amplitude of thermal fluctuations at the binding site and around it. This allows us to draw conclusions about general design rules of allosteric molecules and highlight the controlling feature that biological molecules evolved to optimize their dynamics for their function.\u

Publisher: School of Physics and Astronomy (Leeds)
Year: 2010
OAI identifier:

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  2. (2003). 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures.
  3. (2007). A computational investigation of allostery in the catabolite activator protein.
  4. (1925). A critical study of the direct method of measuring the osmotic pressure of haemoglobin.
  5. (2010). A demonstration of the inhomogeneity of the local dielectric response of proteins by molecular dynamics simulations.
  6. (1993). a global regulatory protein of Escherichia-coli, binds cooperatively to multiple sites and activates transcription of ILVIH.
  7. (2007). A replica exchange Monte Carlo algorithm for protein folding in the HP model.
  8. (2007). A simple physical description of DNA dynamics: quasi-harmonic analysis as a route to the configurational entropy.
  9. (2001). A standard reference frame for the description of nucleic acid base-pair geometry.
  10. (1993). Absolute and relative binding free-energy calculations of the interaction of biotin and its analogs with streptavidin using moleculardynamics free-energy perturbation approaches. Proteins Struct.
  11. (2009). Allosteric modulation of DNA by small molecules.
  12. (2008). Allosteric regulation and catalysis emerge via a common route.
  13. (2008). Allostery and cooperativity revisited.
  14. (2005). Allostery in a coarse-grained model of protein dynamics.
  15. (1984). Allostery without conformational change - a plausible model.
  16. (2008). Allostery: Absence of a change in shape does not imply that allostery is not at play.
  17. (2008). Allostery: DNA does it too.
  18. (2008). Amber version 10.
  19. (2007). An atomic model of the interferon-beta enhanceosome.
  20. (2009). Analysis of cooperativity by isothermal titration calorimetry.
  21. (1998). Analysis of domain motions by approximate normal mode calculations.
  22. (2010). Anisotropic collective motion contributes to nuclear spin relaxation in crystalline proteins.
  23. (1999). Antigen recognition by conformational selection.
  24. (1958). Application of a theory of enzyme specificity to protein synthesis.
  25. (1985). Aspects of symmetry.
  26. (2004). AT islands - Their nature and potential for anticancer strategies.
  27. (1994). Bending and twisting elasticity of DNA.
  28. Beware of density dependent pair potentials.
  29. Binding of molecules to DNA and other semiflexible polymers.
  30. (2000). Binding sites in Escherichia coli dihydrofolate reductase communicate by modulating the conformational ensemble.
  31. (2009). Binding thermodynamics of ferredoxin:NADP(+) reductase: Two di erent protein substrates and one energetics.
  32. (2003). Biological physics; Energy,
  33. (1984). Bonding of molecular-oxygen to T-state human hemoglobin.
  34. (2000). Building-block approach for determining low-frequency normal modes of macromolecules.
  35. (1994). Calorimetric studies of the energetics of protein-DNA interactions in the Escherichia-coli methionine repressor (MetJ) system.
  36. (2005). Changes in calmodulin main-chain dynamics upon ligand binding revealed by cross-correlated NMR relaxation measurements.
  37. (2006). Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution.
  38. (1996). Charge screening and the dielectric constant of proteins: Insights from molecular dynamics.
  39. (2009). CHARMM: The biomolecular simulation program.
  40. Chromatin fiber functional organization: Some plausible models.
  41. (1971). Co-operative binding of nicotinamide-adenine dinucleotide to yeast glyceraldehyde-3-phosphate dehydrogenase.1. Equilibrium and temperature-jump studies at pH 8.5 and 40 degrees
  42. (2004). Coarse-grained model of entropic allostery.
  43. (2005). Coarse-grained models of dynamic allostery in proteins.
  44. (2005). Coarse-grained normal mode analysis in structural biology.
  45. Coarse-graining of condensed phase and biomolecular systems.
  46. (2001). Compaction of single DNA molecules induced by binding of integration host factor (IHF).
  47. (1966). Comparison of experimental binding data and theoretical models in proteins containing subunits.
  48. Conformational and thermodynamic properties of supercoiled DNA.
  49. (2007). Conformational entropy in molecular recognition by proteins.
  50. (2005). Constrained geometric simulation of di usive motion in proteins.
  51. Convergence of molecular dynamics simulations of membrane proteins.
  52. (1998). Cooperative non-specific DNA binding by octamerizing lambda cI repressors: A site-specific thermodynamic analysis.
  53. (2001). Cooperativity in drug-DNA recognition: A molecular dynamics study.
  54. Correlated motions of successive amide N-H bonds in proteins.
  55. Coupling of global and local vibrational modes in dynamic allostery of proteins.
  56. (1996). Crystal structure of the T state of allosteric yeast chorismate mutase and comparison with the R state.
  57. (2005). Cyclization of short DNA fragments and bending fluctuations of the double helix.
  58. (2008). Dealing with structural variability in molecular replacement and crystallographic refinement through normal-mode analysis.
  59. (1998). Deciphering the molecular code of hemoglobin allostery.
  60. (1989). Definitions and nomenclature of nucleic-acid structure components.
  61. (2001). Delineation of the allosteric mechanism of a cytidylyltransferase exhibiting negative cooperativity.
  62. (1995). Determination of DNA persistence length by cryoelectron microscopy - separation of the static and dynamic contributions to the apparent persistence length of DNA.
  63. (1981). Dimeric and tetrameric hemoglobins from the mollusc Scapharca inaequivalis.
  64. (2004). Direct determination of vibrational density of states change on ligand binding to a protein.
  65. (1997). Direct evaluation o thermal fluctuations in proteins using a single-parameter harmonic potential.
  66. (2001). Direct measurement of protein binding energetics by isothermal titration calorimetry.
  67. (1992). Direct mechanical measurements of the elasticity of single DNA molecules by using magnetic beads.
  68. (2003). DNA basepair step deformability inferred from molecular dynamics simulations.
  69. (1998). DNA sequencedependent deformability deduced from protein-DNA crystal complexes.
  70. (1992). DNA twisting and the e ects of noncontacted bases on a nity of 434 operator for 434 repressor.
  71. (1999). DNA-protein cooperative binding through variablerange elastic coupling.
  72. (1988). Domain interaction in rabbit muscle pyruvate-kinase 2. Small angle neutron scattering and computer simulation.
  73. (1997). Dual role of the nuclear factor of activated T cells insert region in DNA recognition and cooperative contacts to activator protein 1.
  74. (2009). Dynamic allostery in the methionine repressor revealed by force distribution analysis.
  75. (2007). Dynamic allostery in the ring protein TRAP.
  76. (2001). Dynamic model of base pair breathing in a DNA chain with a defect.
  77. (2007). Dynamic personalities of proteins.
  78. Dynamic properties of double-stranded DNA by normal mode analysis.
  79. (2005). Dynamical allostery of protein alpha helical coiled-coils.
  80. (2006). Dynamically driven protein allostery.
  81. Dynamics of ligand binding to myoglobin.
  82. (2002). Dynamics of proteins in crystals: Comparison of experiment with simple models.
  83. Einfluss der configuration auf die wirkung derenzyme.
  84. (2010). Elastic network model of allosteric regulation in protein kinase PDK1.
  85. (2002). Elastic properties of proteins: Insight on the folding process and evolutionary selection of native structures.
  86. (2004). ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement.
  87. (2002). Energetics by NMR: Site-specific binding in a positively cooperative system.
  88. (2009). Energetics of allosteric negative coupling in the Zinc Sensor S. aureus CzrA.
  89. (2009). Engineering allostering regulation into biological catalysts.
  90. (2002). Enthalpy-entropy compensation: a phantom phenomenon.
  91. (2003). Enthalpy/entropy compensation: Influence of DNA flanking sequence on the binding of 7-amino actinomycin D to its primary binding site in short DNA duplexes.
  92. (1989). Escherichia Coli cAMP receptor protein: Evidence for three protein conformational states with di erent promoter binding a nities.
  93. (2006). Estimating the configurational entropy from molecular dynamics simulations: anharmonicity and correlation corrections to the quasi-harmonic approximation. Trends Phys.
  94. (1993). Estimation of absolute and relative entropies of macromolecules using the covariance matrix.
  95. (1972). Ethidium bromide as a cooperative e ector of a DNA structure.
  96. (1999). Evolutionarily conserved pathways of energetic connectivity in protein families.
  97. (2006). Fast time scale dynamics of protein backbones: NMR relaxation methods, applications, and functional consequences.
  98. (1999). Folding funnels, binding funnels, and protein function.
  99. (2007). From “simple” DNA-protein interactions to the macromolecular machines of gene expression.
  100. (2008). Function and structure of inherently disordered proteins.
  101. (2006). Fundamentals of biochemistry: life at the molecular level.
  102. (2005). Gene regulation at-a-distance in E-coli: new insights.
  103. (2002). Global allostery model of hemoglobin - Modulation of O-2 a nity, cooperativity, and Bohr e ect by heterotropic allosteric e ectors.
  104. (2008). GROMACS 4: Algorithms for highly e cient, load-balanced, and scalable molecular simulation.
  105. (1995). Hemoglobin allostery -resonance raman spectroscopy of kinetica intermediates.
  106. (2003). Hemoglobin from the leech Macrobdella decora.
  107. (2007). High-throughput modeling and analysis of protein structural dynamics.
  108. (2000). How soft is a protein? A force constant approach to protein dynamics measured by neutron scattering.
  109. (1993). Human deoxyhemoglobin2,3diphosphoglycerate complex low-salt structure at 2.5 Angstrom resolution.
  110. (2003). Increased bending rigidity of single DNA molecules by H-NS, a temperature and osmolarity sensor.
  111. (2008). Influence of DNA structure on adjacent site cooperative binding.
  112. (1992). Intersubunit communications in Escherichia coli cyclic AMP receptor protein: studies of the ligand binding domain.
  113. (2005). Intrinsic dynamics of an enzyme underlies catalysis.
  114. (1998). Introduction To Protein Structure. Garland publishing,
  115. (2006). Ion selectivity in potassium channels.
  116. (2004). Is allostery an intrinsic property of all dynamic proteins? Proteins Struct.
  117. (1999). Is cooperative oxygen binding by hemoglobin really understood?
  118. (1996). Large amplitude elastic motions in proteins from single-parameter, atomic analysis.
  119. (2003). Large-scale millisecond intersubunit dynamics in the B subunit homopentamer of the toxin derived from Escherichia coli O157.
  120. (1972). Ligand binding and internal equilibria in proteins.
  121. (2004). Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR.
  122. (1992). Mapping of spectral density-functions using heteronuclear NMR relaxation measurements.
  123. (2010). Measurement of site-specific C-13 spin-lattice relaxation in a crystalline protein.
  124. (2000). Measuring conformational dynamics of biomolecules by single molecule fluorescence spectroscopy.
  125. (1981). Method for estimating the configurational entropy of macromolecules.
  126. (2008). Methods for calculating the entropy and free energy and their application to problems involving protein flexibility and ligand binding.
  127. (1994). Mode of binding of folate analogs to thymidylate synthase - evidence for 2 asymmetric but interactive substrate-binding sites.
  128. (2008). Model of DNA bending by cooperative binding of proteins.
  129. (1982). Model-free approach to the interpretation of nuclear magnetic-resonance relaxation in macromolecules. 1. theory and range of validity.
  130. (1982). Model-free approach to the interpretation of nuclear magnetic-resonance relaxation in macromolecules. 2. analysis of experimental results.
  131. (2000). Modeling the cAMP-induced allosteric transition using the crystal structure of CAP-cAMP at 2.1 Angstrom resolution.
  132. (2002). Molecular biology of the cell. Garland science,
  133. (1993). Molecular Biophysics, Structure in motion.
  134. (2008). Molecular dynamics simulations of hemoglobin a in di erent states and bound to DPG: E ector-linked perturbation of tertiary conformations and HbA concerted dynamics.
  135. (2002). Molecular mechanisms of chaperonin GroEL-GroES function.
  136. (2001). Molecular Modelling, principles and applications.
  137. (1953). Molecular structure of nucleic acids - a structure for deoxyribose nucleic acid.
  138. (2006). Monte Carlo simulations of biomolecules:
  139. (1993). NMR order parameters and freeenergy - an analytical approach and its application to cooperative Ca2+ binding by calbindin-d(9k).
  140. (1999). NMR-Based amide hydrogendeuterium exchange measurements for complex membrane proteins: Development and critical evaluation. J.Magn.Reson.,
  141. (2006). NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom Normal Mode Analysis. Nucleic Acids Res.,
  142. (2004). Nonlinear physics of DNA.
  143. (1993). Normal mode analysis of G-actin.
  144. (2001). Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol., 339(Part B):204–238,
  145. (2000). Nucleic acids: theory and computer simulation,
  146. oGNM: online computation of structural dynamics using the Gaussian Network Model.
  147. (2001). On the calculation of entropy from covariance matrices of the atomic fluctuations.
  148. (2001). On the dynamic origins of allosteric activation.
  149. (1965). On the nature of allosteric transitions: A plausible model.
  150. (2003). Optimization of tether length in nonglycosidically linked bivalent ligands that target sites 2 and 1 of a Shiga-like toxin.
  151. (1996). Overstretching B-DNA: The elastic response of individual double-stranded and single-stranded DNA molecules.
  152. (1996). Principal component analysis and long time protein dynamics.
  153. (2004). Probing singlestranded DNA conformational flexibility using fluorescence spectroscopy.
  154. (2005). Probing the binding entropy of ligand-protein interactions by NMR.
  155. (2009). Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms.
  156. Protein dynamics explain the allosteric behaviors of hemoglobin.
  157. (2009). Protein dynamism and evolvability.
  158. (2001). Protein flexibility from the dynamical transition: A force constant analysis.
  159. (2001). Protein flexibility predictions using graph theory.
  160. (1992). Protein-induced bending and DNA cyclization.
  161. (1992). Proton NMR-study of the [D(ACGTATACGT)]2-2 Echinomycin complex - conformational-changes between Echinomycin bindingsites.
  162. (2004). Proton-powered subunit rotation in single membrane-bound F0F1-ATP synthase.
  163. (2005). Quantifying allosteric e ects in proteins.
  164. (1998). RecA binding to a single double-stranded DNA molecule: A possible role of DNA conformational fluctuations.
  165. (1993). Refined solution structures of the Escherichia coli trp holo- and aporepressor.
  166. (2007). Refinement of the AMBER force field for nucleic acids: Improving the description of conformers.
  167. (2008). Remote changes in the dynamics of the phosphotyrosine-binding domain of insulin receptor substrate-1 induced by phosphopeptide binding.
  168. (2006). Review - New tools provide new insights in NMR studies of protein dynamics.
  169. (2008). Search strategies in structural bioinformatics.
  170. (2009). Sending signals dynamically.
  171. (2000). Sequence-dependent elastic properties of DNA.
  172. (2000). Sequence-dependent variation in DNA minor groove width dictates orientational preference of Hoechst 33258 in A-tract recognition: solution NMR structure of the 2:1 complex with d(CTTTTGCAAAAG)(2).
  173. (1990). Sequence-specific interaction of Hoechst-33258 with the minor groove of an adenine-tract DNA duplex studied in solution by H-1-NMR spectroscopy.
  174. (1996). Simulating DNA at low resolution.
  175. (2000). Single-molecule studies of DNA mechanics.
  176. (2001). Spin Dynamics: Basics of Nuclear Magnetic Resonance.
  177. (1991). Static and statistical bending of DNA evaluated by Monte Carlo simulations.
  178. (1976). Statistical thermodynamics of random networks.
  179. Steady-state and time-resolved fluorescence studies of conformational changes induced by cyclic AMP and DNA binding to cyclic AMP receptor protein from Escherichia coli.
  180. (1995). Sti chains and filaments under tension.
  181. (1997). Stretching DNA with optical tweezers.
  182. (2001). Structural and functional linkages between subunit interfaces in mammalian pyruvate kinase.
  183. (2009). Structural basis for cAMP-mediated allosteric control of the catabolite activator protein.
  184. Structural dynamics in the C-terminal domain of calmodulin at low calcium levels.
  185. (1984). Structural evidence for ligand-induced sequential conformational changes in glyceraldehyde-3-phosphate dehydrogenase.
  186. (2009). Structural insights into the mechanism of abscisic acid signaling by PYL proteins.
  187. (2000). Structure of apo-glyceraldehyde-3-phosphate dehydrogenase from Palinurus versicolor.
  188. (1990). Structure of deoxyquaternary hemoglobin with liganded with liganded beta-subunits.
  189. (1987). Structure of hologlyceraldehyde-3-phosphate dehydrogenase from Bacillus-Stearothermophilus at 1.8 A resolution.
  190. (2010). Substrate-modulated thermal fluctuations affect long-range allosteric signaling in protein homodimers:
  191. Supercoiling transitions of closed DNA.
  192. (2008). Targeted chemical wedges reveal the role of allosteric DNA modulation in protein - DNA assembly.
  193. (2003). Ten years of tension: single-molecule DNA mechanics.
  194. The allosteric mechanism of yeast chorismate mutase: A dynamic analysis.
  195. (1996). The elasticity of a single supercoiled DNA molecule.
  196. (1999). The propagation of binding interactions to remote sites in proteins: Analysis of the binding of the monoclonal antibody D1.3 to lysozyme.
  197. (1997). The question of long-range allosteric transitions in DNA.
  198. (2004). The relative flexibility of B-DNA and A-RNA duplexes: database analysis.
  199. (2003). The role of dynamics in allosteric regulation.
  200. (2002). The role of dynamics in enzyme activity.
  201. (1996). The structural basis of negative cooperativity: Receptors and enzymes.
  202. (2009). The two active sites of thermotoga maritima CheA dimers bind ATP with dramatically di erent a nities.
  203. (1986). Theory of elasticity.
  204. (1979). Theory of twisting and bending of chain macromolecules: analysis of the fluorescence depolarization of DNA.
  205. (1989). Threedimensional crystal structures of Escherichia coli Met repressor with and without corepressor.
  206. (2001). Time-resolved fluorescence resonance energy transfer: A versatile tool for the analysis of nucleic acids.
  207. (2008). Towards a molecular dynamics consensus view of B-DNA flexibility.
  208. Transmission of allosteric e ects in DNA.
  209. (2001). Two-state allosteric behavior in a single domain signalling protein.
  210. (1904). Uber einen in biologischen beziehung wichtigen Einfluss, den die Kohlen-sauerspannung des Blutes auf dessen Sauersto bindung ubt.
  211. (1997). Understanding DNA - The molecule and how it works.
  212. (2010). Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor.
  213. (1998). Use of capillary electrophoresis in the study of ligand-DNA interactions.
  214. (1998). Vibrational dynamics of folded proteins: Significance of slow and fast motions in relation to function and stability.
  215. (1996). Vmd - visual molecular dynamics.
  216. (2007). What drives proteins into the major or minor grooves of DNA?

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