Designing a Weapon for Biochemical Warfare

A month or so ago, I had my Chemical Biology 2 fortnightly workshop. Our task was, in groups, to design or re-design a binding protein using an unnatural amino acid. Being as I am, I led my group to a very dark place and suggested we re-design haemoglobin to create a biochemical weapon that would introduce the mutation into populations. Here's the report I had to write for it:

Report 3: Designing a binding protein

Haemoglobin, as a binding protein for oxygen and thus an integral molecule for respiration and survival, could be redesigned via the incorporation of an unnatural amino acid such that respiration is dysfunctional to the point of death. By incorporating this re-design of the binding protein via an engineered virus into targeted organisms, haemoglobin could be used as a biological weapon for warfare.

The underlying concept behind this re-design towards dysfunction is to incorporate an unnatural amino acid to overstabilise the conformation of oxygen-bound haemoglobin, such that these oxygen molecules cannot be released into oxygen-depleted tissues. This would, effectively, suffocate infected organisms from within their own bodies. This concept is similar to the mechanisms of carbon monoxide poisoning, whereby the binding of CO to one monomer of the tetramer increases the affinity of its other monomers to oxygen, preventing their release into tissues. However, in this case, we are altering the binding protein, haemoglobin, itself so that this ‘poisoning’ can occur without the introduction of a toxin such as carbon monoxide. As previously eluded, this modification to haemoglobin will ideally be introduced into target organisms through a virus that inserts a gene encoding for the altered dysfunctional haemoglobin, including, if necessary, genes encoding for the production of machinery such as tRNA for the incorporation of the unnatural amino acid.

Energetically speaking, our goal was is to introduce an unnatural amino acid into haemoglobin to alter its conformational landscape, such that the new landscape has an immensely deep well when oxygen is bound. This would mean that the haemoglobin would be very unlikely to possess the energy required to traverse this conformational landscape out of the well to release oxygen. Ideally, we would only have to incorporate a change into one monomer of the tetramer where oxygen cannot be released means that the other monomers’ affinity for oxygen is also increased to the point of impossibility of release. This is similar to the poisoning mechanism of carbon monoxide.

In terms of engineering this protein, it is obvious that we cannot do laboratory-directed evolution – we’re trying to reduce, not improve, function, the opposite of natural selection, which means that we cannot use selective screening  to filter out our desired proteins. Since we are targeting one monomer, with ideally only one replacement of an amino acid with an unnatural amino acid, we can conduct targeted mutagenesis for our purposes, with a screening mechanism that, perhaps, monitors the concentration of blood within a solution (if in vitro) or E. Coli cell (if in vivo). Targeted mutagenesis is ideal in this situation, because we know the exact protein structure that we’re modifying. In addition, we could also closely examine the mechanism behind carbon monoxide’s binding to haemoglobin, to find an amino acid that could best imitate the effect of carbon monoxide. In this manner, we could choose an unnatural amino acid that is best suite, and then experiment with its position in the protein sequence.

In this way, haemoglobin, integral to much animal life, could be re-designed to be the bearer of death. When perfected, the virus could be used as a biological weapon by introducing it into target populations. However, for warfare purposes, the uncontrollable spread of viruses must be considered, and an antidote to the virus available for the home population.

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I ended up getting 80%, an HD for it. These were the comments, which i think are very true, and which I kind of knew as I was writing it, but didn't care

Enjoyable read, I think you may have got a bit carried away with the concept more than the underlying science, but you did explain the idea in terms of conformational dynamics and protein engineering well.

I also ended up getting an ANU crush confession out of it??