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I do agree with this but would add that you wouldn't want to do static docking to a single protein and sidechain configuration anyway so you're bound to find a
by l33tman 5y ago
I do agree with this but would add that you wouldn't want to do static docking to a single protein and sidechain configuration anyway so you're bound to find a usable forcefield. The incoming structure (ideally!) only needs to fall into the right energy landscape valley. If your forcefield and MD simulation can't keep this stable within the natural protein's configuration space you are probably not going to make progress, and you need the simulations to evaluate the natural energy landscape at body temperature, not cryo temperature.
There are some examples of this issue in the AlphaFold blog, some protein loops that they thought were mispredicted but it turned out they were part of an energy degeneracy so the natural state fluctuated pretty wildly, so if you can't simulate this properly it matters less how accurate the incoming structure is (to a certain degree of course).
- timr 5y agoI think we largely agree. Any drug target of any real-world interest is going to have local motion (i.e. floppiness that is dependent on circumstance and time) that matters at least as much to the finding of a drug than the fold of the protein itself. One place I hesitate here is that step 0 to doing that kind of a simulation is having a decent starting structure. So maybe protein folding can help there. But I'm also skeptical, because the quality of the structure matters a great deal to getting a good simulation. A bad/blurry structure is of marginal use.