Of Cabbages, Kings, and Paratopes

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Podcast: Of Cabbages, Kings, and Paratopes
Length: 4 min 42 seconds
Written and read by the author

Diocletian was both an adept emperor and expert cabbage farmer. We find many examples of people having diverse and unrelated talents. Antibodies also display an affinity for diverse and unrelated proteins. The body produces antibodies against the surface proteins of a pathogen. A single protein molecule represents hundreds to thousands of locations where the antibodies can bind. We label these binding locations, epitopes. The corresponding site on the antibody is the paratope.

Often when discussing the process of making a specific antibody to a specific antigen, we are referring to the Maturity Affinity Process for IgG antibodies. To simplify the tight antigen-antibody fit, we talk about a “lock and key” scenario. This analogy highlights the unique close fit, but also leads us away from several fundamental truths about paratopes. Despite being made for an epitope, paratopes are not defined by their epitopes. A single antibody’s paratope binds many different epitopes on diverse, unrelated proteins. At face value, this appears incorrect but let’s examine how this binding works, and we will see why we need to look beyond the lock and key scenario.

Roughly five amino acids comprise an epitope. The paratope blankets this with 15 amino acids with the center five providing most of the binding power. When any protein repeats these five amino acids in the same sequence, the risk for binding occurs. The surrounding ten amino acid landscape to the center five, can weaken or strengthen the bond.

Much more than this though is that the Variable Region of the antibody, the portion where the paratope lies, represents roughly 50 amino acids.  Consider how many groups of 15 you can make from 50. While the immune system creates an antibody with one paratope in mind, by design, it reacts with varying levels of affinity with hundreds to thousands of different proteins. Yet the potential that any antibody will react with a random protein is still thousandths of a percent. Thus, we can still consider antibodies specific to an antigen. At the same time, Random Paratope Coupling explains: false positive point-of-care tests, false positive or low titer results for other blood tests, and antibodies to antigens the body hasn’t seen before.