Visualizing Protein-Ligand Unpaired Interactions

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

Difficulty level

Download

Download code

unpairedmap2img.py

See also Usage subsection.

Solution

The depict_unpairedmap 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 OERenderUnpairedInteractionMap function generates an image that displays the clash and unpaired interactions detected in the ligand and in nearby residues.
6. The legend associated with the unpaired map is rendered by invoking the OEDrawUnpairedInteractionMapLegend function.

def depict_unpairedmap(image, protein, ligand, opts, legend_frame=None):
    """
    :type image: oedepict.OEImageBase
    :type protein: oechem.OEMolBase
    :type ligand: oechem.OEMolBase
    :type opts: oedepict.OE2DMolDisplayOptions
    :type legend_frame: oedepict.OEImageBase
    """

    # 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)

    if legend_frame is not None:
        lopts = oegrapheme.OE2DActiveSiteLegendDisplayOptions(12, 1)
        oegrapheme.OEDrawUnpairedInteractionMapLegend(legend_frame, adisp, lopts)

Usage

Usage

unpairedmap2img.py

The following commands will generate the image shown in Figure 1.

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

Command Line Parameters

Simple parameter list
    -height : Height of output image
    -width : Width of output image

    SplitMolComplex options :
      -covalentligand : Split covalent ligands
      -ligandname : Ligand name

    molecule display options :
      -aromstyle : Aromatic ring display style

    input/output options :
      -complex : Input filename of the protein-ligand complex
      -protein : Input filename of the protein
      -ligand : Input filename of the ligand
      -out : Output filename of the generated image

    active site display options:
      -interactive-legend : Visualize legend on mouse hover (SVG feature)

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 OERenderUnpairedInteractionMap 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.

  Table 2. Examples of visualizing atom clash(es)

  See also

  • OEClashInteractionHint class in the OEChem TK manual

• 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.

  Table 3. Examples of visualizing unpaired hydrogen bond interactions

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

  See also

  • OEHBondInteractionHint class in the OEChem TK manual
  • OEHBondInteractionHintType namespace in the OEChem TK manual

• 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

  Table 4. Examples of visualization hydrogen bond clash interactions

  donor-donor clash	acceptor-acceptor clash

  See also

  • OEHBondInteractionHint class in the OEChem TK manual
  • OEHBondInteractionHintType namespace in the OEChem TK manual

• 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.

  Table 5. Examples of visualizing unpaired salt-bridge interactions

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

  See also

  • OESaltBridgeInteractionHint class in the OEChem TK manual
  • OESaltBridgeInteractionHintType namespace in the OEChem TK manual

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).

Table 6. Example of visualizing protein-ligand unpaired and clash interactions before and after optimizing hydrogen positions

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

See also

• OEPlaceHydrogens function in the OEChem TK manual
• Protein Preparation chapter in the OEChem TK manual

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.

Table 2. Example of visualizing unpaired and active site interaction maps

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

Related Python Cookbook Recipes

• Visualizing Protein-Ligand B-factor
• Visualizing Protein-Ligand B-factor Map
• Visualizing Protein-Ligand Contacts
• Visualizing Protein-Ligand Interactions
• Visualizing Protein-Ligand Maps

See also in OEChem TK manual

Theory

• Biopolymers chapter
• Protein Preparation chapter

API

• OEInteractionHintContainer class
• OEPerceiveInteractionHints function
• OEPlaceHydrogens function

See also in OEDepict TK manual

Theory

• Molecule Depiction chapter

API

• OEImage class

See also in Grapheme^TM TK manual

API

• OE2DActiveSiteDisplay class
• OEDrawUnpairedInteractionMapLegend function
• OEPrepareActiveSiteDepiction function
• OERenderUnpairedInteractionMap function