does the minimization calculation with the --minimize flag include the energy of specified flexible residues

[charlie clark]

Hi,

I'm running minimization of ligands against a receptor using --minimize and I'm also specifying which sidechains should be flexible with --flexres.

As soon as I started using --flexres I noticed the free energy scores improved dramatically but the ligands don't seem to be in much more favourable positions (and in many cases, seem as if they would bind much less favorably). In cases where this happen the flexible sidechains do seem to have much less free energy so I suspect that the free energy calculation is incorporating the free energy of all specified flexible sidechains, regardless of if they are involved with the the ligand.

Is this the case? And if so, is there a way to allow for sidechain flexibility but still get the affinity of just the ligand (so that the free energy of a ligand binding a static receptor could be fairly compared with the free energy of a ligand binding the same receptor but with flexible residues enabled?)

Thanks a lot for all your help.
Charlie

[charlie clark]

apologies, have just seen that my first question has been answered in https://sourceforge.net/p/smina/discussion/help/thread/cef2d93015/

I still am unsure about my second question, however - is it possible to separate the free energy scores of the ligand from the flexible receptor sidechains interatcting with the receptor?

[David Koes]

The short answer is not easily. You need to reassemble the receptor structure and then run score_only on the ligand and this structure. As a sanity check you can also score only with flexible residues turned on. Take the difference to get the flexible only contribution.

[charlie clark]

Thank you. Are you aware of any method that could be used to stitch the flexible residues into the original receptor structure? I'm willing to do the scripting but am unable to assign the new coordinates to the correct atoms as the pdb outputs for the flexible residues are redundant (e.g. all carbon atoms are called C rather than CA, CG, etc...)

[David Koes]

https://github.com/gnina/gnina/blob/master/scripts/makeflex.py