The new work shows that the detailed time course of the breathing motions allows ACh to bind almost as fast as if the channel were always open. Importantly, this work also shows that the motions discriminate against the binding of possible substrates that are larger than the natural substrate ACh. The researchers have very nicely combined analytic theory and simulations to yield a physically interesting result. Zhou, a theoretical biophysicist, performed an analysis of the statistics of a long simulation of AChE dynamics. He found that although the channel to the active site is open wide enough to admit the substrate ACh only 2.4 percent of the time, the breathing is rapid enough to assure that whenever there is substrate about, it will likely be able to slip through to the active site during one of the openings.
Larger substrates require larger openings of the channel, which occur less frequently.
Such substrates are therefore more likely to diffuse away from AChE before they can enter the active site and react. He is the developer of many of the computer simulation methods that permit this close scrutiny of the dance of the molecules. The nanosecond-long molecular dynamics simulation was performed by Houston's Wlodek. He began the work on an Intel Paragon machine at SDSC, using high-speed connections from Texas. The Paragon was then one of the world's largest machines, and a 5-picosecond chunk of the simulation took about 10 hours on 128 processors.