The ribosome is an enormous, complicated RNA machine. We are asking you, intrepid players, to stabilize it. We’ve made a lot of noise about how this could enable new chemistry. But why is that? I wanted to give a brief, no-background-necessary sketch of the chemistry and physics underlying why that is.
Enzymes (whether made of protein or RNA) are a type of catalyst. A catalyst lowers the “activation energy” of a reaction, which allows it to go faster. (Properly, “happen more often”; it’s not like bond breaking and forming can be truly ‘sped up’, but rather that particles bump into each other all the time but usually nothing happens.)
How can a catalyst lower a reaction’s activation energy? Two points. First, “activation energy” is made out of two components: the “delta-H,” or change in “enthalpy,” and (temperature times) the “delta-S,” or change in “entropy.” In order to lower a reaction’s activation energy, it either has to make the change in enthalpy more favorable or it has to make the change in entropy more favorable. (It can do both, but generally speaking, catalysts do one or the other.)
OK, so a catalyst either makes the change in enthalpy more favorable or the change in entropy more favorable. The enthalpy of a particular molecular state is (essentially, for our purposes) its internal energy: the energy of its bonds, the nice intermolecular forces it’s experiencing, etc.) The entropy is a little more complicated because it’s a measure of the disorder of a system. In some sense, it’s a way of saying “how specifically you have described the system.” If you say “two molecules, within a really huge box,” that is a very high-entropy state (high disorder) compared to “two molecules, RIGHT NEXT TO EACH OTHER.”
So first, let’s compare each of these quantities for a bond-forming reaction like the formation of a peptide bond. Enthalpically speaking, the transition state is terrible. All the bonds that are going to break during the course of the reaction are “half-broken” and all the bonds that are going to form are “half-formed.” Colloquially, we are getting none of the benefit and all of the pain. It’s the worst. So if you could form nice interactions with the transition state, that would make the terrible, costly delta-H a little better. A lot of catalysts do just this: many reactions, especially in biology, proceed via acid-base catalysis where one group donates a proton to another, making it a better leaving group. (Look up serine proteases for an example.) Entropically, the transition state is also terrible! Remember my example of a low entropy state? In order to form all those bonds, you have to take two molecules that were once wild and free and force them right next to each other for as long as the reaction takes.
So, here’s the big kicker: if the ribosome were reducing the delta-H of the reaction by stabilizing the transition state, that would be a bit frustrating for us because you’d need intricately different ribosomes for EVERY reaction. But that’s not what it does! The ribosome reduces the delta-S of the reaction by DESTABILIZING the reactants. That’s right: entropically, the transition state is hopeless – both reagents are constrained – so the ribosome makes the entropy of the starting materials worse by forcing them together (they’re chemically bonded to tRNAs, and the ribosome binds tRNAs very tightly). This is a very general mechanism – I didn’t have to tell you anything about the identity of the reactants – so we suspect that the ribosome could be made to function as a general, programmable synthesis device if we figure out how to accommodate each reagent in other places. (For example, there is an “exit tunnel” where the growing polymer chain gets extruded, like those dolls with play-doh for hair. If your monomer is too bulky for that tunnel, bad news.)
And if we can make the ribosome REALLY stable, we can play around with these critical areas and start to hollow them out if we need to, without risking the whole ribosome falling apart.
Thanks for reading! Let me know if there’s anything I can clean up to make this a clearer introduction to our theory.