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• Visualizing Protein-Ligand Unpaired Interactions new

# Visualizing Protein-Ligand Unpaired Interactions new¶

## Problem¶

You want to visualize protein-ligand unpaired and clash interactions. See example in Figure 1.

Figure 1. Example of visualizing protein-ligand unpaired and clash interactions (PDB: 1NQ2)

## Ingredients¶

 OEChem TK - cheminformatics toolkit (including OEBio TK) OEDepict TK - molecule depiction toolkit Grapheme TK - molecule and property visualization toolkit

## Solution¶

The DepictUnpairedMap illustrates how simple it is to generate these images.

1. OEInteractionHintContainer object is constructed that stores information about possible interactions between the ligand and the protein.
2. The interactions are perceived by calling the OEPerceiveInteractionHints function.
3. The active site is then prepared for 2D depiction by invoking the OEPrepareActiveSiteDepiction function.
4. When the OE2DActiveSiteDisplay object is constructed, residues are positioned around the ligand close to those atoms which they are interacting with.
5. The OERenderUnpairedInteractiopnMap function generates an image that displays the clash and unpaired interactions detected in the ligand and in nearby residues.
  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 def depict_unpairedmap(image, protein, ligand, opts): # perceive interactions asite = oechem.OEInteractionHintContainer(protein, ligand) if not asite.IsValid(): oechem.OEThrow.Fatal("Cannot initialize active site!") asite.SetTitle(ligand.GetTitle()) oechem.OEPerceiveInteractionHints(asite) # depiction oegrapheme.OEPrepareActiveSiteDepiction(asite) adisp = oegrapheme.OE2DActiveSiteDisplay(asite, opts) oegrapheme.OERenderUnpairedInteractionMap(image, adisp) 

Usage:

prompt > wget https://files.rcsb.org/download/1nq2.pdb
prompt > python3 unpairedmap2img.py -complex 1nq2.pdb -out 1nq2.svg


## Discussion¶

### Interaction perception¶

Currently the OEPerceiveInteractionHints function perceives the following interaction types:

Table 1. Interaction types currently available in OEChem TK
name corresponding interaction class corresponding interaction type namespace
cation-pi OECationPiInteractionHint OECationPiInteractionHintType
chelator OEChelatorInteractionHint OEChelatorInteractionHintType
clash OEClashInteractionHint None
contact OEContactInteractionHint None
covalent OECovalentInteractionHint None
halogen bond OEHalogenBondInteractionHint OEHalogenBondInteractionHintType
hydrogen bond OEHBondInteractionHint OEHBondInteractionHintType
salt-bridge OESaltBridgeInteractionHint OESaltBridgeInteractionHintType
stacking (T and Pi) OEStackingInteractionHint OEStackingInteractionHintType

The default geometric parameters used by the OEPerceiveInteractionHints function have been set based on literature data ([Kumar-2002], [Cavallo-2016], [Bissantz-2010], and [Marcou-2007] ). The interaction parameters can be customized by using the OEPerceiveInteractionOptions class.

### Unpaired interaction depiction¶

The OERenderUnpairedInteractiopnMap function currently visualizes the following interactions detected by the OEPerceiveInteractionHints function.

• Atom clash interaction

When visualizing protein-ligand atom crashes, red outline of a residue circle indicates that there are one or more atoms in that residue which are too close to some ligand atom(s). Clashing ligand atoms are marked with a red arc that is directed towards the corresponding clashing residue. The red shading on the grey line representing the shape of the pocket is used to identify atom clashes easily.

See also

• Unpaired types of the hydrogen bonding interaction

An unpaired hydrogen bond interaction is detected:

• if there is no ligand/protein acceptor atom that could interact with a protein/ligand donor atom
• if there is no ligand/protein donor atom that could interact with a protein/ligand acceptor atom

Different linker types are used to mark unpaired acceptor and donor hydrogen bond interactions. Please note that since these interactions are unpaired, the direction of the linkers has no real spatial meaning. Ligand linkers are directed away from the ligand, while protein linkers are directed towards the ligand.

 unpaired ligand acceptor unpaired protein acceptor unpaired ligand donor unpaired protein donor

See also

• Clash types of the hydrogen bonding interaction

A hydrogen bond clash interaction is detected:

• if an acceptor ligand atom interacts with an acceptor protein atom
• if a donor ligand atom interacts with an donor protein atom
 donor-donor clash acceptor-acceptor clash

See also

• Unpaired types of the salt-bridge interaction

An unpaired salt bridge interaction is detected if there is a positively / negatively charged functional group either in the ligand or in nearby protein without a matching negatively / positively charged functional group, respectively.

Different linker types are used to mark unpaired positive and negative salt-bridge interactions. Please note that since these interactions are unpaired, the direction of the linkers has no real spatial meaning. Ligand linkers are directed away from the ligand, while protein linkers are directed towards the ligand.

 unpaired ligand positive unpaired protein positive unpaired ligand negative unpaired protein negative

See also

### Hydrogen position optimization¶

Since the interaction perception dependents on the position of hydrogens, it is highly recommended to optimize those positions prior to perceiving the interactions. The two images below reveal the effect of optimizing the hydrogen bond network in a protein-ligand complex: less atom clash(es) and less unpaired hydrogen bond interaction(s).

 original complex downloaded from PDB Database (PDB 1D3H) complex after optimizing hydrogen positions

See also

### Unpaired map vs active site interaction map¶

An unpaired interaction map provides a complementary view to the more common active site interaction map. While the interaction map (on the right) depicts interactions between the ligand and protein, the unpaired map (on the left) illustrates interactions that could contribute to binding but are not formed in the complex. Together, these two maps of the protein-ligand binding site provide insights into protein-ligand interactions and communicate complex 3D structural results to medicinal chemists in a directly actionable way.

 unpaired interaction map (PDB 1BR6) active site interaction map (PDB 1BR6)

Theory

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Theory

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