MOE/DivCon QMScore & QB-PWD Analysis

MOE/DivCon QMScore & QB-PWD Analysis

QuantumBio’s patented QMScore method and pairwise energy decomposition (PWD) method have been published and validated on numerous structures in both academia and industry. The interested reader is strongly encouraged to consider these publications. To summarize, the QMScore method itself is based on the thermodynamic cycle where the various terms detailed below are summed together in order to determine the ∆Gsb.

Once the simulation is complete, the mdb file created in the previous step will have the following components available. These parameters are detailed within the QMScore papers noted above. Three different overall scores are provided including QMScore, the Electronic Interaction Energy, and finally the mixed QM-empirical Molecular Recognition Model score. Generally, these three scores will correlate with one another.

  • QMScore: The total QMScore value associated with the ligand.
  • dHf_g: Gas phase heat of formation.
  • Solv_elec: The electrostatic portion of the solvation free energy.
  • LJ_att: Dispersion interactions from the attractive/dispersive part of the classical Lennard-Jones interaction potential.
  • S_solv: Solvent component of the entropic contribution to binding.
  • S_vib: Conformational component of the entropic contribution to binding.
  • E_eInt: Electronic Interaction Energy
  • MRMScore: Molecular Recognition Model score.
  • E_stericMRM: Steric component of the Molecular Recognition Model score.
  • E_elecMRM: Electrostatic component of the Molecular Recognition Model score.
  • E_solvMRM: Pairwise solvation component of the Molecular Recognition Model score.

QM-PWD Analysis and Heatmap

In addition to QMScore, the PairWise energy Decomposition (PWD) scheme for evaluating the interaction energy using the neglect of nonbonded differential overlap (NNDO) formalism applied to study protein-ligand interaction has been implemented within the DivCon package. This scheme permits the calculation of the self-energy of the atom, core- electron interactions, electron-electron repulsion, and exchange between atoms from the molecular electron density. This PWD data is provided within the h5 file that is generated by DivCon over the course of the simulation. The h5 file is required in order to capture this data, and should be handled along with the MOE mdb file. The PKA-PKB example discussed on this page is available here and the interested reader is encouraged to download this tar.gz file – and the enclosed mdb and h5 files – and follow along.

In order to view the PWD Heatmap, choose the QuantumBio->PWD Analysis dialog box. Load the AstexSet.mdb file using the Load button. Once the data is loaded, press the Apply button to perform the PWD analysis.

Concurrent with the Load process is a sequence/structure alignment using the MOE Pro Align tool. In the event that the target structures came from different X-ray structures, this alignement will align the active sites of the structures treated. Pressing the SEQ button in the upper right hand corner of the MOE window will display the aligned sequences. For the Astex set (sequence displayed below), most of the targets are identical or almost identical with one another. However, the 37th, 38th, and 39th target sequences show a gap at the 47th amino acid. As noted in the paper associated with this data, there were several structures that differed in some way from one another.

Once the structure is loaded and the Apply button has been pressed, the View button next to the Interaction Heat Map will be active. Press the View button in order to view this map.

When the view button is pressed, the structure in the window will “zoom in” on the active site/ligand, and create a surface. The surface is colorized the match the heatmap shown below where the while spaces are no interaction and the blue spaces are significantly attractive.

The interaction map lists the ligands vertically along the left hand side, and the key active site amino acids horizontally along the bottom. The rectangles within the map are colored based on the attractive nature the corresponding ligand/amino acid interaction. The ligand rectangles are “clickable” and clicking each of these ligands will switch the molecule within the viewer. The surface is likewise updated to reflect the colors of the map for that particular ligand. The two black rectangles for the 37th and 39th ligand represent the above noted sequence gaps. Along the bottom of the interaction map box there are buttons that can be used to further manipulate the surface on the screen. Specifically, the number of sigmas, number of colors, and number of ticks increase or decrease the resolution of the data on the screen. The radius represents the radius of the surface as documented in the MOE documentation. The following buttons provide additional functionality:

Apply: Any changes in the resolution of the data or the radius of the surface must be applied in order to take effect.

Animate: In the PKA-PKB structure in this example, there are almost 45 different structures available in the mdb file. The Animate button step to each of structures in the mdb file and display the structure along with the corresponding surface.

Print and Save: Once the interaction heatmap is configured as desired, the Print and Save buttons are used to print the heatmap or save it to a file.

Close: Close the heatmap display.

Standard MOE interface elements can be integrated with the DivCon interface and PWD analysis. For example, the Ligand Interactions dialog box (depicted below) will automatically update if it is open when the new ligand is chosen in the heatmap. The Ligand Interactions dialog box is documented within the MOE documentation, and provides a two-dimensional view of the ligand within the active site.

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