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
5. THE WONDERFUL WORLD OF G PROTEINS AND G PROTEIN–COUPLED RECEPTORS
6. DYNAMICS OF MWC MOLECULES: ENZYME ACTION AND ALLOSTERY
7. HEMOGLOBIN, NATURE’S HONORARY ENZYME
8. HOW CELLS DECIDE WHAT TO BE: SIGNALING AND GENE REGULATION
9.BUILDING LOGIC FROM ALLOSTERY
10. DNA PACKING AND ACCESS: THE PHYSICS OF COMBINATORIAL CONTROL
11.ALLOSTERY EXTENDED
12. MAXWELL DEMONS, PROOFREADING, AND ALLOSTERY
13. A FAREWELL TO ALLOSTERY
INDEX

A signature feature of living organisms is their ability to carry out purposeful actions by taking stock of the world around them. To that end, cells have an arsenal of signaling molecules linked together in signaling pathways, which switch between inactive and active conformations. The Molecular Switch articulates a biophysical perspective on signaling, showing how allostery—a powerful explanation of how molecules function across all biological domains—can be reformulated using equilibrium statistical mechanics, applied to diverse biological systems exhibiting switching behaviors, and successfully unify seemingly unrelated phenomena.

Rob Phillips weaves together allostery and statistical mechanics via a series of biological vignettes, each of which showcases an important biological question and accompanying physical analysis. Beginning with the study of ligand-gated ion channels and their role in problems ranging from muscle action to vision, Phillips then undertakes increasingly sophisticated case studies, from bacterial chemotaxis and quorum sensing to hemoglobin and its role in mammalian physiology. He looks at G-protein coupled receptors as well as the role of allosteric molecules in gene regulation. Phillips concludes by surveying problems in biological fidelity and offering a speculative chapter on the relationship between allostery and biological Maxwell demons.

Appropriate for graduate students and researchers in biophysics, physics, engineering, biology, and neuroscience, The Molecular Switch presents a unified, quantitative model for describing biological signaling phenomena.