Preconception: FlexX placements are sometimes found at the rim of the active site.
True — but only in the past!
Since FlexX Release 2, such scenarios now belong in the past: since FlexX Release 2, access_scaling has been turned on by default. This very powerful parameter downscales energy contributions of exposed hydrogen bond formers and consequently, placements are much more restricted to deeper parts of the pocket.
In addition in Release 2, we have introduced another facility to "smoothly" guide the placements to user-defined regions. The scheme is based on a depth calculation, a subsequent Gaussian smear-out, and a ligand-receptor Gaussian overlap calculation.
A script could look like this:
SET FILTER_GAUSS 1 # this activates the filtering
LIGAND
READ my_ligand_file
RECEPTOR
READ my_protein_rdf_file
RECEPTOR
GAUSS
CGRID # this creates a depth grid in the active site
SELGRA 2 0 # option to show the grid when the receptor is drawn
DRAW
DISPLAY # launches FlexV, our graphics engine
WAIT # waits for you to press RETURN to continue
CCONSTR 0.999 # creates Gaussian filter functions (high threshold)
SELGRA 0 2 # select the Gaussians to be shown at draw
DRAW 1 # draws the Gaussian functions
WAIT # now pick the Gaussian function for which the
# overlap shall be considered and a minimum overlap,
# e.g.;
#
SELGAUSS 1 13,14 y 200 y *
# here ^ you can even specify SMARTS patterns to match!
DOCKING
COMPLEX ALL
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| Figure 2: The grid creation; color coding is dependent on the depth of the pocket: the deeper buried, the darker the color |
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Figure 1: The Gaussian functions created according to grid
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Here are results on 1a4g, a viral neuraminidase:
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Release 2 standard: a set of spread-out
poses |
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| Release 2 with Gaussian Filter: The solutions are fully constrained to lie deeply buried. |
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In fact, the best scoring solution on rank 1 exhibits an RMSD of 1.2Å. The same solution was on rank 4 before!
In a later step, you can transform your Gaussian functions into FlexX-Pharm spatial constraints. The keyword to check in the user guide is TOPHARM. ;-)
And as always: Please do contact us if you have chronic problems with your FlexX dockings! We wish you much success with your FlexX!
watch the movie
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