Nerve agents are scary molecules. Thankfully, there is an antidote for pretty much anything, but only if taken at the right time (recall all those old Hollywood action movies…). There is a very interesting Swedish structural biology paper that describes molecular-level interactions between a series of nerve agents and their target – acetylcholinesterase (AChE). Nerve agents are fairly simple organophosphorous compounds that wreak havoc by covalent modification of Serine-203 in the active site of AChE. HI-6 is an oxime-containing antidote for several types of phosphorous-containing nerve agents. This oxime is remarkably efficient, acting as a competing nucleophile that reacts with the phosphorus center of the modified AChE, thereby restoring its normal enzyme activity. Is there a better way to demonstrate the marvels of chemistry? Everything here makes sense from the standpoint of simple polar interactions. Below I am showing a crystallographic view of Russian VX-modified AChE as well as the reaction of HI-6 that restores enzyme activity. The paper is remarkable because it also provides evidence why HI-6 fails with certain kinds of nerve agents such as tabun (tabun-modified Serine-203 is shown in the box). Apparently, the Phe338/His447 array close to Serine-203 reduces the conformational mobility in the tabun-AChE complex. The steric interactions interfere with the approach of oxime-pyridinium group of HI-6 to the phosphorus atom of the adduct. The kinetics of reactivation are thereby significantly slower and other (smaller) antidotes need to be designed.