The Molecular Switch: Signaling and Allostery

Cover
Contents
Preface
PART I: THE MAKING OF MOLECULAR SWITCHES
	1. It’s An Allosteric World
		1.1 The Second Secret of Life
		1.2 The Broad Reach of the Allostery Concept
			1.2.1 Sculpting Biochemistry via Allostery
			1.2.2 One- and Two-Component Signal Transduction and the Two-State Philosophy
		1.3 Reasoning about Feedback: The Rise of Allostery
			1.3.1 The Puzzle
			1.3.2 The Resolution of the Molecular Feedback Puzzle
			1.3.3 Finding the Allosterome
		1.4 Mathematicizing the Two-State Paradigm
			1.4.1 Transcendent Concepts in Physics
			1.4.2 One Equation to Rule Them All
		1.5 Beyond the MWC Two-State Concept
			1.5.1 Molecular Agnosticism: MWC versus KNF versus Eigen
		1.6 On BeingWrong
		1.7 Summary
		1.8 Further Reading
		1.9 References
	2. The Allosterician’s Toolkit
		2.1 A Mathematical Microscope: Statistical Mechanics Preliminaries
			2.1.1 Microstates
			2.1.2 The Fundamental Law of Statistical Mechanics
			2.1.3 The Dimensionless Numbers of Thermal Physics
			2.1.4 Boltzmann and Probabilities
		2.2 Case Study in Statistical Mechanics: Ligand–Receptor Binding
			2.2.1 Ligand Binding and the Lattice Model of Solutions
		2.3 Conceptual Tools of the Trade: Free Energy and Entropy
			2.3.1 Resetting Our Zero of Energy Using the Chemical Potential
		2.4 The MWC Concept in Statistical Mechanical Language
		2.5 Cooperativity and Allostery
			2.5.1 Cooperativity and Hill Functions
			2.5.2 Cooperativity in the MWC Model
		2.6 Internal Degrees of Freedom and Ensemble Allostery
		2.7 Beyond Equilibrium
		2.8 Summary
		2.9 Further Reading
		2.10 References
PART II: THE LONG REACH OF ALLOSTERY
	3. Signaling at the Cell Membrane: Ion Channels
		3.1 How Cells Talk to the World
		3.2 Biological Processes and Ion Channels
		3.3 Ligand-Gated Channels
		3.4 Statistical Mechanics of the MWC Channel
		3.5 Data Collapse, Natural Variables, and the Bohr Effect
			3.5.1 Data Collapse and the Ion-Channel Bohr Effect
		3.6 Rate Equation Description of Channel Gating
		3.7 Cyclic Nucleotide–Gated Channels
		3.8 Beyond the MWC Model in Ion Channelology
			3.8.1 Conductance Substates and Conformational Kinetics
			3.8.2 The Koshland-Némethy-Filmer Model Revealed
			3.8.3 Kinetic Proliferation
			3.8.4 The Question of Inactivation
		3.9 Summary
		3.10 Further Reading
		3.11 References
	4. How Bacteria Navigate the World around Them
		4.1 Bacterial Information Processing
			4.1.1 Engelmann’s Experiment and Bacterial Aerotaxis
			4.1.2 Love Thy Neighbors: Signaling between Bacteria
		4.2 Bacterial Chemotaxis
			4.2.1 The Chemotaxis Phenomenon
			4.2.2 Wiring Up Chemotaxis through Molecular Switching
		4.3 MWC Models of Chemotactic Response
			4.3.1 MWC Model of Chemotaxis Receptor Clusters
			4.3.2 Heterogenous Clustering
			4.3.3 Putting It All Together by Averaging
		4.4 The Amazing Phenomenon of Physiological Adaptation
			4.4.1 Adaptation by Hand
			4.4.2 Data Collapse in Chemotaxis
		4.5 Beyond the MWC Model in Bacterial Chemotaxis
		4.6 The Ecology and Physiology of Quorum Sensing
			4.6.1 Wiring Up Quorum Sensing
			4.6.2 Dose-Response Curves in Quorum Sensing
			4.6.3 Statistical Mechanics of Membrane Receptors
			4.6.4 Statistical Mechanics of Membrane Receptors with Inhibitors
			4.6.5 Data Collapse in Quorum Sensing
		4.7 Summary
		4.8 Further Reading and Viewing
		4.9 References
	5. The Wonderful World of G Proteins and G Protein–Coupled Receptors
		5.1 The Biology of Color
			5.1.1 Crypsis in Field Mice
			5.1.2 Coat Color and GPCRs
		5.2 The G Protein–Coupled Receptor Paradigm
		5.3 Paradigmatic Examples of GPCRs
			5.3.1 The ß-Adrenergic Receptor
			5.3.2 Vision, Rhodopsin, and Signal Transduction
			5.3.3 Light as a Ligand: Optogenetics
		5.4 G Protein–Coupled Ion Channels
		5.5 Summary
		5.6 Further Reading and Viewing
		5.7 References
	6. Dynamics of MWC Molecules: Enzyme Action and Allostery
		6.1 Enzyme Phenomenology
		6.2 Statistical Mechanics of Michaelis-Menten Enzymes
		6.3 Statistical Mechanics of MWC Enzymes
			6.3.1 Modulating Enzyme Activity with Allosteric Effectors
			6.3.2 Competitive Inhibitors and Enzyme Action
			6.3.3 Multiple Substrate Binding Sites
			6.3.4 What the Data Say
		6.4 Glycolysis and Allostery
			6.4.1 The Case of Phosphofructokinase
		6.5 Summary
		6.6 Further Reading
		6.7 References
	7. Hemoglobin, Nature’s Honorary Enzyme
		7.1 Hemoglobin Claims Its Place in Science
			7.1.1 Hemoglobin and Respiration
			7.1.2 A Historical Interlude on the Colouring Matter
			7.1.3 Hemoglobin as a “Document of Evolutionary History"
		7.2 States andWeights and Binding Curves
		7.3 Y oh Y
		7.4 Hemoglobin and Effectors: The Bohr Effect and Beyond
		7.5 Physiological versus Evolutionary Adaptation: High Fliers and Deep Divers
		7.6 Hemoglobin and Competitors: Carbon Monoxide Fights Oxygen
		7.7 Pushing the MWC Framework Harder: Hemoglobin Kinetics
		7.8 Summary
		7.9 Further Reading
		7.10 References
	8. How Cells Decide What to Be: Signaling and Gene Regulation
		8.1 Of Repressors, Activators, and Allostery
		8.2 Thermodynamic Models of Gene Expression
		8.3 Induction of Genes
		8.4 Activation
			8.4.1 Binding of Inducer to Activator
			8.4.2 Binding of Activator to DNA
			8.4.3 Activation and Gene Expression
		8.5 Janus Factors
		8.6 Summary
		8.7 Further Reading
		8.8 References
	9 Building Logic From Allostery
		9.1 Combinatorial Control and Logic Gates
		9.2 Using MWC to Build Gates
			9.2.1 Making Logic
			9.2.2 A Tour of Parameter Space
		9.3 Beyond Two-Input Logic
		9.4 Summary
		9.5 Further Reading
	10. DNA Packing and Access: The Physics of Combinatorial Control
		10.1 Genome Packing and Accessibility
		10.2 The Paradox of Combinatorial Control and Genomic Action at a Distance
		10.3 Nucleosomes and DNA Accessibility
			10.3.1 Equilibrium Accessibility of Nucleosomal DNA
		10.4 MWC Model of Nucleosomes: Arbitrary Number of Binding Sites
		10.5 Nucleosome Modifications and the Analogy with the Bohr Effect
		10.6 Stepping Up in Scales: A Toy Model of Combinatorial Control at Enhancers
		10.7 An Application of the MWC Model of Nucleosomes to Embryonic Development
		10.8 Summary
		10.9 Further Reading
		10.10 References
PART III: BEYOND ALLOSTERY
	11. Allostery Extended
		11.1 Ensemble Allostery
			11.1.1 Normal Modes and Mechanisms of Action at a Distance
			11.1.2 Integrating Out Degrees of Freedom
		11.2 Ensemble Allostery through Tethering
			11.2.1 Biochemistry on a Leash
			11.2.2 Random-Walk Models of Tethers
		11.3 Irreversible Allostery
		11.4 Summary
		11.5 Further Reading
		11.6 References
	12. Maxwell Demons, Proofreading, and Allostery
		12.1 Demonic Biology
		12.2 A Panoply of Demonic Behaviors in the Living World
			12.2.1 The Demon and Biological Specificity
			12.2.2 Making Stuff Happen in the Right Order
			12.2.3 The Free-Energy Cost of Demonic Behavior
		12.3 Overcoming Thermodynamics in Biology: Kinetic Proofreading
			12.3.1 Equilibrium Discrimination Is Not Enough
			12.3.2 The Hopfield-Ninio Mechanism
			12.3.3 Proofreading Goes Steampunk: Building Proofreading Engines
		12.4 Summary
		12.5 Further Reading
		12.6 References
	13. A Farewell to Allostery
		13.1 Diversity and Unity: Diverging and Converging Views of Biology
		13.2 Shortcomings of the Approach
		13.3 Beyond Allostery
		13.4 Further Reading
		13.5 References
Index