Some while ago I had a discussion with the head of an internationally renowned neuroscience group about the use of thermodynamics in biology. He told me that he has heard from a close biophysicist friend (also a very prominent scientist) that thermodynamics is not applicable on the scale of single molecules. This is because it is a macroscopic theory that refers to average quantities on large scales. I was somewhat surprised by this statement because life is so obviously sensitive to temperature and other thermodynamic variables. It never came to my mind that anyone could doubt the central role of thermodynamics even on a molecular scale. But according to my colleagues, thermodynamics is a theory about macroscopic averages only - and a single molecule doesn’t know about averages - since it is only one single molecule which is always in one particular state at a time. Isn’t that obvious?
No, this is not obvious. In fact, it is terribly wrong!
There exist many prejudices about thermodynamics. The “thermo” in thermodynamics suggests that it mostly deals with temperature or heat, but in fact this is only one aspect of it. It also deals with pressure, electrostatic potentials, chemical potentials and pH-values. It deals with binding constants and reaction kinetics, charging of membrane capacitors and flows of ions. Thermodynamics is not only about averages but also about distributions and fluctuations. The fluctuation aspect is particularly important because it defines the magnitude of susceptibilities such as heat capacity, compressibility and capacitance. Fluctuations can also be big on very small scales. Motion on the atomic scale defines the temperature, and one can observe the associated fluctuations as Brownian motion and diffusion.
Thermodynamics is everywhere. It is applicable to the universe and to nuclear particles. It is more than a theory, it is rather the language of physics. It defines what we mean by energy, pressure and temperature. In his scientific autobiography from 1949, Albert Einstein wrote: “Therefore the deep impression which classical thermodynamics made upon me. It is the only physical theory of universal content concerning which I am convinced that, within the framework of the applicability of its basic concepts, it will never be overthrown.”
Or as another colleague of mine put it: „Thermodynamics is like a good red wine. The older you get, the more you appreciate it.“ Getting older might eventually turn out to be problematic, but this is just increase in entropy - another important concept in thermodynamics. And honestly, what should be wrong with a glass of a good red wine?
For the above reasons, I believe that thermodynamics is the physics equivalent to wisdom.
Thermodynamics is everywhere. It is applicable to the universe and to nuclear particles. It is more than a theory, it is rather the language of physics. It defines what we mean by energy, pressure and temperature. In his scientific autobiography from 1949, Albert Einstein wrote: “Therefore the deep impression which classical thermodynamics made upon me. It is the only physical theory of universal content concerning which I am convinced that, within the framework of the applicability of its basic concepts, it will never be overthrown.”
Or as another colleague of mine put it: „Thermodynamics is like a good red wine. The older you get, the more you appreciate it.“ Getting older might eventually turn out to be problematic, but this is just increase in entropy - another important concept in thermodynamics. And honestly, what should be wrong with a glass of a good red wine?
For the above reasons, I believe that thermodynamics is the physics equivalent to wisdom.
Let's go back to single molecules and take the binding constant of a drug to a receptor protein as an example (see figure below). The binding constant corresponds to the equilibrium constant in the mass action law, which represents the ratio of the probabilities to find a bound or an unbound form of the drug. This law has been derived assuming that the chemical potentials of the drug in solution and the drug bound to the receptor are equal - which is one of the consequences of the second law of thermodynamics. The second law states that in equilibrium the intensive variables (temperature, pressure, …, but also the chemical potentials) are uniform in space and time.
The equilibrium constant corresponds to a Boltzmann-factor in the distribution of states from statistical thermodynamics, which depends on temperature, pressure and all other intensive variables. The concentrations in the mass action law (e.g., the concentration of a drug in the cytosol of a cell) correspond to probabilities to find a molecule in a given state. Similarly, the pH is related to the probability to find a proton. Here, we have not even mentioned that each molecule is surrounded by water and ion clouds, i.e., that in biology a single molecule does not even exist.
The equilibrium constant corresponds to a Boltzmann-factor in the distribution of states from statistical thermodynamics, which depends on temperature, pressure and all other intensive variables. The concentrations in the mass action law (e.g., the concentration of a drug in the cytosol of a cell) correspond to probabilities to find a molecule in a given state. Similarly, the pH is related to the probability to find a proton. Here, we have not even mentioned that each molecule is surrounded by water and ion clouds, i.e., that in biology a single molecule does not even exist.
Schematic drawing of the binding of drugs to receptors. Picture from Wyatt Pyzynski (Wikipedia)
Therefore, even on the scale of single molecules we always talk about statistics, ensembles and average probabilities to find a certain result in an experiment. The equilibria between folded and unfolded proteins, the cooperative binding of oxygen to hemoglobin or the denaturation of the DNA upon heating are other examples for the application of thermodynamics on single molecular scale.
Thus, by using equilibrium constants and adjusting pH values and temperature, every molecular biologist implicitly acknowledges that thermodynamics is valid on the scale of individual molecules.
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