Has reversed engineering been done on known protein to find where the lowest movement would produce the greater change in energy?
We could find the strongest ligand and allow them less movement and allow more movement to weaker ligands.

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I've never had a biology class in a post-secondary level (beyond my recent Biophotonics) so I can't comment reliably on the science involved. However, my impression has been that the energy gradient (measure of how fast the energy would move as related to the position of the links) primarily depends on position, not on the actual material (amino acid).

If that's the case, then this method would be worthless since what we are doing now is trying to optimize the program for work on UNKNOWN proteins. Without prior knowledge of the best configuration, there would be no way to tell which ligands to weight in which direction.

Since the position of the amino acids is so important, even if there is a significant effect from the amino acids themselves, it would likey be shadowed by the position of the final protein. My (admittedly poor) intuition tells me that the final position of each link would have much more effect on the energy gradient.

Again, it would be a great idea if they were trying to optimize the program to be able to find the structure of known proteins for whatever reason. However, since it ultimately won't be used with a "native" or known protein, there would be no way to find the final energy gradient.

Another approach might be to find the energy gradient at each step and simply move each link towards the lowest energy. This is impractical though, since the resulting optimization function would have so many degrees of freedom, that there would be an astronomical number of local minimums -- so many that you wouldn't get anywhere CLOSE to the lowest possible energy state. In order to jerk the system out of each local minimum, you'd have to use the random jumping that's done now. The whole process would take much more computation time for little or no improvement in performance!

Anyway, some of that is just my intuition talking, but I DO have a lot of experience in optimizing systems (primarily in lens design) and enough math study to fill my head many times over. It's quite possible that I'm vitally misunderstanding the processes involved in the makeup of proteins, and I'd welcome correction!

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