Greetings,
I have created a number of 100ns ligand and enzyme simulations in which the simulation begins with my ligand within the binding pocket, then over the course of anywhere from 5-20ns the ligand will leave the binding pocket. I realize that optimally the ligand should never leave the binding pocket (especially since my specific ligand inhibits by means of covalent binding); however from what I understand from running unbiased simulations statistically the 1:1 enzyme:ligand interaction is transient when considering the entropy of the system. Should the ligand perform the covalent interaction and stay bound? If so what should I do to optimize my ligand further to allow for the covalent reaction to take place? Should I desalt it (which I never originally did) or optimize it further with charmms (it already had good scores according to cgenff). How is running a biasing potential--which will find the lowest binding energy docking conformation--different from what I am performing--especially as I have already optimized my ligand binding coordinates with autodock?
I appreciate your time,
Brendan
--Please see attached pdf with embedded animations for reference
https://www.biorxiv.org/content/10.1101/650440v2.full
Perhaps this can be useful.
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