Docking to RNA via RMSD-driven Energy Minimization with Flexible Ligands and Flexible Targets

Christophe Guilbert and Thomas L. James

The following are Supplemental Materials to illustrate flexible docking using MORDOR.

    Each image is actually a movie (gif animate) which should automatically start when you open this web page , if for  some reasons, the image is static, you can directly click in the image to download the movie in quick time format.

Docking Procedure

1j7tThis is an illustration of MORDOR docking procedure for the A-site on 16S robosomal RNA from E. Coli complexed with the aminoglycoside paromomycin (PDB code 1j7t). The following movie shows a few docking steps  "step 1 and 2" as descrived in the manuscript at the " Docking via MORDOR" section. 

The first step consists of placing one heavy atom of the  ligand at one of the "hot spots" on the receptor which are defined by a spheres (not seen). The orientation of the ligand is defined  by one of the 120 orientations uniformly distributed on a trigonometric sphere. At this stage , the receptor is held rigid. this stage can be easily identified in the movie since the receptor is not moving.  The 120 orientations are tested and quickly minimized to remove any clash. Each time we find a "good" orientation while trying all the possible orientations, we allow the ligand to explore the receptor surface using PEDC (Path Exploration with DIstance Constraints) algorithm (download article in pdf) enabling an induced fit of both the ligand and the receptor while the ligand probe the receptor.
This procedure is repeated 120 time for all the orientations and for all the heavy atoms in the ligand.

The following examples are not link to the manuscript but illustrate well the PEDC algotithm. 

Example Igif image

Here is a flexible docking example using a region of the ribosomal 16S RNA (pdb ID: 1fjf.pdb) to re-dock the antibiotic paromomycin into its (known) binding pocket. The ligand in blue color is the drug position as defined by the experimental X-ray structure. Note the adaptation of the receptor as the ligand explores the groove. The drug is “walking” along the surface mainly following the major groove. One can clearly see that the ligand during the search procedure binds specifically to the location found experimentally. The ligand bound in this position has the best binding interaction energy. However, it can still explore other possible binding sites.

Example IIgif animate

    This example shows the “induced fitting” ability of MORDOR when docking a potential ligand to an RNA (telomerase) structure where there is no prior experimental binding information. The ligand initially approaches one of the sphere-identified “hot spots” (not seen) at the surface of the RNA before exploring the macromolecular surface. One can see that the compound briefly explores a pocket before (almost instantaneously) intercalating between two bases, forming a nice stacking interaction with them.