This is why RNA (and the mRNA vaccines) are unstable and must be kept cold.ĭNA differs from RNA by one oxygen atom (3). Hydrogen does not promote this hydrolysis. (Right) DNA has a hydrogen atom (red) circle in the same location of the hydroxyl group in RNA. This promotes the breaking of the phosphate bond (red hatch line) that holds RNA together, (Middle) A cyclic intermediate (which is unstable and reacts with water, completing the hydrolysis) and an RNA fragment (green box) are formed. (Left) As in Figure 5, RNA has a hydroxyl group 5 atoms from phosphorous putting it at just the right bonding distance of phosphorous (blue arrow). It's anachiometric assistance again, this time with phosphorous instead of carbon (Figure 6).įigure 6. What does this have to do with unstable RNA vaccines?Ī lot. This is an example of neighboring group participation. First, the 4-hydroxybutyric acid methyl ester reacts with itself to form gamma-butyrolactone. This reacts with water (green hatch line) to complete the hydrolysis reaction. The reaction of 4-hydroxybutyric acid methyl ester to gamma-butyrolactone is promoted by the hydroxyl group. When the hydroxyl (OH) group is 5 atoms from the carbonyl group it is within perfect bonding distance to react with the carbonyl (C=O) group (Figure 5).įigure 5. Now you can see why I've drawn the stupid molecule this way. They are drawn in different configurations, but it's still the same molecule. Good luck.īoth of these figures are different representations of the same molecule. Things should be starting to get ugly right about now. This is one reason people hate chemistry.įigure 4. If you haven't hung yourself by now, bear with me and I'll show you what all this gibberish has to do with RNA.įigure 4 demonstrates the concept of neighboring group participation, but why the difference? It makes no sense. Comparative hydrolysis rates of two esters. This is called anchimeric assistance (or neighboring group participation) and its effect can be significant (Figure 3).įigure 3. I'll be as gentle as possible.Īnchimeric assistance (Neighboring group participation): Why RNA is unstable.įor reasons best left unstated, when a hydroxyl group (1) is either five or six atoms away from either the C=O (carbonyl, carbon-oxygen double bond) or P=O (phosphoryl, phosphorous-oxygen double bond) group where a reaction is taking place, that reaction is accelerated. I apologize in advance, but we're going from organic 101 to organic 401. What does any of this have to do with the instability of the Pfizer vaccine? The blue hatch line shows the bond that is broken in the reaction. The red squares show where the water has been added. The process (Figure 2) is conceptually identical to that of esters.įigure 2. ![]() ![]() Phosphate esters, the backbone of DNA and RNA, can also be hydrolyzed. The red boxes show where the water has been added. ![]() Hydrolysis of an ester forms a carboxylic acid and an alcohol. What is going on is actually a rather simple, well-known chemical reaction called ester hydrolysis – the breaking of an ester bond by water, producing a carboxylic acid and an alcohol (Figure 1)įigure 1. Hence, it should come as no surprise that it's time for TDCLFH! TM In the interest of boring all of you to death, I figured it might be a good (?) idea to look at this instability at the molecular level. Alex Berezow recently wrote about the instability of the Pfizer vaccine.
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