Defiance is the Secret of Life�Energy for Fun and Profit
MCB137/237 – Spring 2025
Jacques Monod and the Second Secret of Life
Monod’s Second Secret of Life: Allostery
… But If Allostery Is the Second Secret of Life, What Is the First one?
… But There Are Also Other Contenders
Fidelity in biological polymerization: Key question, are we surprised?
The Insufficiency of Equilibrium Molecular Recognition
What Is the Energy of DNA Pairing?�Intuition from PCR Primer Design
A Toy Model of Translation
The Kinetic Proofreading Idea: Energy to Fuel Error Correction
Translation Does Indeed Require Energy
Life Is Defiance�What Can You Do Only When You Spend Energy?
Life Is Defiance�What Can You Do Only When You Spend Energy?
Viruses Are Constantly Evolving�Tracking Influenza
Tracking the Spread of Coronavirus
Tracking the Spread of Coronavirus
Influenza Evolves Faster Than SARS-CoV-2
Viral Genome Lengths
Mahmoudabadi and Phillips (2018)
A Compromise Between Genome Length and Mutation Rate
Holmes, PNAS (2010)
ssRNA+ Viral Genome Lengths
Gorbalenya et al. (2006)
SARS-CoV-2 +ssRNA Genome
Exonuclease Is Present Only in Viruses With Genomes > 20 kb
Smith & Denison (2012) https://doi.org/10.1016/j.coviro.2012.07.005
Exonuclease Provides Proofreading Activity To SARS-CoV
Eckerle et al., PLoS Pathogen (2010)
The Unreasonable Effectiveness of Statistical Mechanics Models of Bacterial Decision Making
Garcia and Phillips, PNAS (2011);
Brewster et al., Cell (2014); Weinert et al., PRL (2014)
Statistical Mechanics Assumes�No Energy Consumption
Life Is Defiance�What Can You Do Only When You Spend Energy?
The Nature of Life is Confusing:�The Example of Diffusion
Jean Baptiste Perrin, 1909
Robert Brown, 1828
Humpty Dumpty and the Cost of Irreversibility
Humpty Dumpty sat on a wall,�Humpty Dumpty had a great fall.�All the king's horses and all the king's men�Couldn't put Humpty together again
Can We Run the Movie of Life Backwards?
The Birth of Maxwell’s Demon
But if we conceive a being whose faculties are so sharpened that he can follow every molecule in its course, such a being, whose attributes are still as essentially finite as our own, would be able to do what is at present impossible to us. For we have seen that the molecules in a vessel full of air at uniform temperature are moving with velocities by no means uniform, though the mean velocity of any great number of them, arbitrarily selected, is almost exactly uniform. Now let us suppose that such a vessel is divided into two portions, A and B, by a division in which there is a small hole, and that a being, who can see the individual molecules, opens and closes this hole, so as to allow only the swifter molecules to pass from A to B, and only the slower ones to pass from B to A. He will thus, without expenditure of work, raise the temperature of B and lower that of A, in contradiction to the second law of thermodynamics.
From a letter from Maxwell to Tait
Running the Movie of Life Backwards… …If You Are Willing to Pay!
A Huge Amounts of Energy Stored Around Us
Demonic Biology
Our Intuition About Spatial Scales in Biology�(22 orders of magnitude)
Our Intuition About Temporal Scales in Biology�(29 orders of magnitude)
What’s Our Intuition About Energy Scales in Biology?�(43 orders of magnitude!)
Estimate: How Much Energy from Sunlight Hits the Earth in a Day?
What Is the Daily Energy Consumption of a Human?
What Is the Daily Energy Consumption of a Human?
What Is the Daily Energy Consumption of the Human Poulation?
How Much Energy to Build an E. coli cell?
Energy to Build a Protein
Concentrations and Absolute Numbers in Your Favorite Cell Type
Deterministic Versus Thermal Energies�Using Dimensionless Numbers to Get a Sense of Scale
Energy Can Be Converted Between Multiple Forms
Some Examples of Energy Conversion
Human Scheme for Energy Generation
Plant Scheme for Energy Generation
A Hierarchy of Biological Batteries
Molecular Batteries Powering the Cell
Where the Energy Comes From Is None of Your Business!
A Hierarchy of Biological Batteries
Stouthamer’s Analysis of ATP Usage in Bacteria
Energy Requirements Scale With Cellular Volume
Lynch and Marinov (2015)
Synthesizing ATP
ATP Synthase
Rotating at the speed of a jet engine
Synthesizing ATP: Your turn
Number of ATP Synthases in the Cell
Competition Between Surface Area and Volume in Cellular Energetics
Competition between ATP Consumption and Production Versus Cell Size
An Hypothesis: Mitochondria Circumvent the Competition Between Surface Area and Volume
Concentrations and Absolute Numbers in Your Favorite Cell Type
Musings on Entropy and Life
``The entropy of the whole universe must be increasing. It follows that each of us, as a living organism that locally and temporarily decreases entropy, must produce somewhere in the world around us an increase in entropy. As we metabolize food, for example, we give off heat and increase random molecular motion around us. In a sense, we buy our lives through the entropic death of the universe.'' - Mathews & van Holde (1990), Biochemistry (Prentice Hall).
Defying Diffusion
Denomic Diffusion
The Demon Has to Fight Against Membrane Permeability
Harvesting the Energy Paid by the Demon�The Proton Motive Force
ATP Synthase
Measuring ATP Synthase Rotation
A Simple Model of Membrane Potential and Proton Transport
The ATP Synthase Converts Energy Stored in the Proton Gradient Into ATP
Harnessing Concentration Gradients to Do Work
LacY from the lac Operon Pumps Lactose Into the Cell
LacY Harnesses the H+ Gradient to Pump Lactose In
Symporters Act As AND Gates
Symporters Harness Ion Gradients to Facilitate Molecular Transport
Nsugar = 3
Nion = 8
Nsugar = 9
Nion = 4
Nsugar = 2
Nion = 7
Nsugar = 10
Nion = 5
The exchange made in the cellular economy
A Hierarchy of Biological Batteries
Energy in ATP Hydrolysis
Where Does the Energy in ATP Hydrolysis Come From?
Searching for Non-Equilibrium Signatures in Cellular Decision Making
A Closer Look at Translation Error Rates
The Wider Problem of Molecular Recognition
HP Model of Proteins: A Toy Model to Explore Fidelity
Molecular Recognition in Translation
A Simple Model of Amino Acid Incorporation
Energetics of Codon Recognition
Molecular Recognition
But Error Rates Are Much Lower Than Predicted by Thermodynamics
Need a Maxwell Demon That Defies Thermodynamics
Rob Phillips
The Kinetic Proofreading Idea
Translation Consumes Energy
A Simplified Model of Kinetic Proofreading
Prominence of One-Way Arrows in Our Cartoon Models of Biology
Biological Assemblies Call for One-Way Arrows
Energy Expenditure Makes It Possible to Encode for Temporal Ordering of Events
A Simplified Model of Kinetic Proofreading
Allostery�Relating Hydrolysis to Mechanical Work
The Demon in the Piston
The Allosteric Transition Gives One More Opportunity for Ligand Discrimination
Waiting Time Distributions of Correct and Incorrect Ligand Unbinding
Revealing Translational Dynamics Using Stochastic Simulations
Confirming Our Prediction About the Fraction of Errors in Translation
Stochastic Simulations�One of the Three Protocols for Solving Biological Dynamics
Trajectories and Probabilities of the Constitutive Promoter
The Stochastic Simulation Protocol
Stochastic Simulation of the Constitutive Promoter
A Hierarchy of Biological Batteries
Life Is Defiance�What Can You Do Only When You Spend Energy?
Prominence of One-Way Arrows in Our Cartoon Models of Biology
Biological Assemblies Call for One-Way Arrows
Energy Expenditure Makes It Possible to Encode for Temporal Ordering of Events
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