Heme 6/13/22

Science with Richard Bleil

Hemoglobin, as I’m sure you know, is the protein in red blood cells that transports oxygen to the cells, and carbon dioxide away from the cells and into the atmosphere where it causes global warming to kill us all.  Oh, sorry, cross purposes there.  Hemoglobin actually has four protein components, giving rise to a quaternary structure needed to perform its function.  Inside the hemoglobin is a “prosthetic group”, called heme, meaning it’s attached to the hemoglobin but is not one of the amino acids that typically make up proteins.  Heme is a flat organic molecule, with an iron in the center of it.  The heme allows access to the iron from both sides of the heme plate, allowing each heme molecule (and its corresponding iron) to carry two oxygen diatomic allotropes or carbon dioxide molecules at a time.  Each hemoglobin protein actually has four heme molecules, so each hemoglobin can carry eight species total. 

The heme molecule is not well understood even today.  Quantum mechanical simulations always underestimate the strength with which oxygen or carbon dioxide (or carbon monoxide) will bind to the iron in these electron rich heme molecules.  The problem with these quantum simulations is that there’s a rather severe restriction on the total number of atoms that can be included in the simulation and completed in a reasonable (and useful) time frame.  These calculations take a very long time and immense computational power (I used to run them on the national Cray supercomputer).  Because we cannot include the entire hemoglobin protein, the obvious assumption is that the protein itself somehow acts as an electron feeder or dampener in the heme, modifying its electronic behavior and accounting for the differences between the quantum mechanical estimates of bonding strength, and experimental values.

Some years ago, a friend had procured a grant to run calculations on the heme molecule.  She was doing a post-doc at the same institution where I was, but she had procured the grant for the project while in graduate school at another institution.  Her proposal was to do calculations on the heme molecule itself, without the iron.  She wanted to use simulations to estimate thermodynamic data such as enthalpy and entropy.  Enthalpy is just the energy of the molecule, and entropy is the chaos. 

She told me that the team she was working with had gotten on her nerves, and she refused to include their names on the paper.  It should have been a warning to me.  But I agreed to help her complete the work so she could get a publication from it.  She agreed that in return she would list me as a co-author, but in reality, I was little more than an advisor in the thermodynamics of the results, so I wasn’t sure I was doing enough to constitute a co-authorship.  Still, that’s kind of the way academia works these days, so if she wanted to list me, that was fine.

Without the iron, though, heme must include two hydrogen atoms.  The iron is held in place by four nitrogen atoms with a special kind of bonding called “coordinate covalent”.  The iron is positively charged, so without the iron, the heme has extra electrons, giving it a negative two charge.  Thus, two hydrogens are normally included to neutralize this charge, and the hydrogens exist at cross nitrogens.  That is, if you orient the heme molecule so two nitrogens are on the top and bottom of the cavity that normally holds the iron, then the other two hydrogens would be to the left and to the right.  Two are vertical, two are horizontal.  The hydrogens, then, might be attached to the two vertical nitrogens (which is arbitrary since you can simply rotate the molecule to change them to horizontal or anywhere in between).  Thus, they are opposite each other. 

So, here’s the problem that she didn’t see.  As she was a biochemist, she really didn’t understand how chemical calculation simulations worked, nor did she understand entropy as I do with my background in statistical thermodynamics.  Because the hydrogens could be oriented either horizontally or vertically, this introduces an additional source of entropy that the simulation doe not, cannot, really understand or incorporate.  The heme molecule is highly symmetrical, so the calculations would result in exactly the same values either way that you orient the hydrogens.  But this represents a new element of uncertainty, or entropy if you prefer.  That means that the entropy calculations will be off.  Statistical thermodynamics tells us that the amount the entropy will be off is exactly k*ln(2), where k is Boltzmann’s constant, with a well-known value.

I explained this to my friend.  But, as I’ve seen in other biochemists, she opted to believe the computer results.  Including this additional amount in the entropy would have taken a very small paragraph, but she was so upset that I didn’t believe the simulation values that she, you guessed it, decided not to give me credit.  Well, that’s fine.

Sometimes it’s hard to think of scientists as emotional, but they’re really living breathing human beings.  If you read academic articles today, they are extremely dense, and very unemotional, as the authors try to pack as much information in with as few words as possible (probably because they have to pay to publish their articles, which is illogical since you also have to pay to read them).  There was a day, however, when scientists very much included emotions and feelings.  If you read Charles Darwin’s original paper, you’ll see that he addresses how his hypothesis is antithetical to religious dogma, and actually apologizes for doing so.  Other old articles (maybe a century ago) included jabs at other scientific names, including insults to their mothers.  I must admit, those articles are more fun to read.

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