Now you see ’em…

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Mar 27, 2019

I thought I’d present my thoughts to you in a slightly more formal way today. Thus, my attempt at a manuscript in blog format:

Protons are interesting

C.M. Goodman

Abstract: Protons are bizarre little things, aren’t they?

Introduction: This train of thought started when I spotted this interesting paper in JACS from Hans-Heinrich Limbach and colleagues about figuring out what protons are doing in enzyme active sites. In particular, they use an aprotic solvent system as a model to figure out how the pKa of the NH in the pyridine ring of PLP (basically vitamin B6) is affected by an intermolecular (protein to PLP) hydrogen bond. The lack of water in both the alternate solvent system and the active site, then, similarly serve to modulate the pKa of the hydrogen.

Introduction part 2: The additional fuel for this thought process comes from another great teacher I had, Craig Martin, who taught one of my graduate school classes on biomolecular structure. In one of the first classes, he asked us, “Why does DNA form a double helix?” He let us go on and on about the base stacking, and the specific hydrogen bonds that form between the complimentary base pairs, etc., and then finally told us that it’s all because of water (and the entropy thereof). Base stacking could still happen without a duplex, and the bases could form hydrogen bonds with water molecules, but the good ol’ H2O would be restricted, and so the double helix is better for all involved.

Results: uh… I’ve got nothing.

Discussion: This paper and Dr. Martin’s wise words got me thinking about how little I really think about protons and water, and thus sent my train of thought into a station I like to call ’What’s going on there?’ Aside from people who are really 100% focused on what water is doing (i.e., what the structure of water is, etc.), and that alternate group of people who are doing insanely water-sensitive reactions (and thus have to worry about water ALL THE TIME), how much do you all really think about how water is affecting the surface of your protein, or the conformational equilibria of peptides or natural products, or so on? What other scenarios require an all out consideration of water? And how will uncovering the structure of water change the way that we think about this topic, or it is so specific for each case that we’ll always be searching for a better understanding of water? Finally, what are the best (or at least your favorite) ways to track down what protons are doing?

Conclusion: Ok – all this talk of water has gotten me really thirsty. I’m off to the water fountain…

Catherine (associate editor, Nature Chemical Biology)

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