Swollen Phase Peptide Synthesis VR

Everyone has heard of Solid Phase Peptide Synthesis but not everyone knows that it is much better called Swollen Phase because the lightly-linked beads swell in the solvent and swell even more as the peptide chain grows. Amazingly, the polymer chains in the support actively assist the process by interfering with the natural tendency of many peptides to self-associate.

Instructions are below.

We have a lightly cross-linked chain of polystyrene (PS) beads in white. To them we add a number (NAA) of amino acids (AA) up to 20. The resulting starting structure is too symmetric to be realistic, but a randomized starting conformation is notoriously hard to set up for such simulations. With the Touchpad button, or by pointing and clicking at the Pause control we set the simulation going. With the Triggers one can fly forward or backward in the direction of view, allowing a full exploration of any aspect of the structure that takes your interest.

At startup the defaults are that the PS-PS, AA-AA and AA-PS interactions are "neutral", meaning that chains are free to wander through space, limited only by the covalent interactions along the chain. If, say, the PS-PS interaction is increased (point, click the trigger and slide) then the PS chains start to prefer each other. Setting the PS-PS value to less than zero means that they prefer to be away from each other. The same applies to the other interactions

If the AA-AA value is relatively high then we see a clustering of the peptides. If they fully clustered then they would fall out of solution. The key to SPPS is that the PS chain actively gets in the way of such clustering. So peptides that are insoluble in the solvent being used, are kept in relatively free motion by the interference from the PS chains.

This can be verified by clicking the Invis option. This makes the AA unaware of the PS (except at the point of covalent attachment) and clustering becomes so intense that you can imagine the peptide falling out of solution. As is common in all such simulations, if you de-select the option, there can be a numerical "explosion" of AA and PS that are "inside" each other, so you might see fragments flying away. This is just an unfortunate artefact.

Credits

The idea for the app, and the exposition of the science behind it came from Prof Stephen Kent at U Chicago. He was one of the pioneers who helped transform Merrifield's Nobel Prize winning idea from lab scale to a multi-kg high-purity synthetic tool used around the world today. Some basic statistics shows that even the most brilliant SPPS synthesis will cease to be effective beyond, say, 70 AA. Prof Kent developed the technique ("native chemical ligation") for taking two (say) 70 AA peptides and combining them rather effortlessly to a single 140 AA peptide, making it possible to synthesise seriously large peptides and proteins used both in science and medicine.

It has been a real pleasure to work with him and to follow his guidance to go from a crude prototype to an impressive scientific demonstration of some key principles that continue to be misunderstood by many who use SPPS.