11. BindingSite Analysis:

Protein Function

 

Protein function

• A protein is not a standalone system.

• The coordinated action of several proteins controls how cells function.

• Ligands, such as tiny chemical compounds, interact with proteins, nucleic acids, and other proteins.

 

3D-Figure 1. PDB structure of 5EMC is of  Transcription factor GRDBD and smGRE complex with Two chains B [auth A],
C [auth B] of sequence length 94 (CLICK me for more info!!).

 

3D-Figure 2. PDB structure of 4UDC is of  GR in complex with dexamethasone with chain A of sequence length 280 (CLICK me for more info!!).

 

Binding site

Defined portion of the protein surface involved in the interaction with a ligand or a macromolecule.

 

 

 

Intermolecular Interactions

• Van der Waals forces

• Hydrogen bonds

• Salt bridges

• Hydrophobic effect

 

Diversity of binding sites

Proteins interact with:

• Proteins

• Nucleic acids

• Ligands

Different type of interactions require different binding sites

Below 3D interactive view gives us a model of  :

• PDB ID: 4DXA
  Rapl in complex with KRIT1
  Res: 1.95 A

 

Ligand binding site: deep cleft
PPI: flat and large surface

 

Recognition determinants

• Geometrical complementarity (Size and shape)

• Physicochemical complementarity (specific interactions)

• Pocket volume: 600-900 ų
  Drug-like molecule volume: 400 ų

• Specific amino acids occur more frequently in BindSites (R, H, W, Y)

 

Protein flexibility

Flexibility of the binding site may result from:

• rotating the side chains

• structural reorganization (backbone movement)

To accommodate various ligands, the binding site may need to adopt a varied conformation (induced fit).

Where performing binding site analysis, it is desirable to take into account various 3D protein structures (when available).

 

Binding site identification

A co-crystallized ligand can quickly locate a protein's binding site.

• What if there are no co-crystallized ligands available?

• What happens if we want to investigate brand-new binding sites (allosteric sites)?

It has become possible to locate binding sites inside a protein structure using computational methods.

two divisions:

• Algorithms based on geometry

• Energy-efficient algorithms

 

Algorithms based on geometry

Use just geometric criteria to identify solvent-accessible areas embedded in the protein surface. virtual sphere fitting (e.g. Site Finder)

Algorithms based on energy

Calculate the energy of the interaction between a probe and a protein.

 

Druggability

What qualifies a protein as a viable therapeutic target?

• The protein and the relevant illness are related.

• The binding of a tiny chemical can alter how biologically active a protein is.

How to tell if a protein can be drugged:

• Find a binding pocket, then check to see if it can bind compounds similar to drugs.

 

What makes a BindingSite druggable?

physical, chemical, and structural characteristics that encourage the binding of tiny molecules with high specificity and affinities.

the following factors: size, shape, and flexibility.

Define a BindingSite's druggability by contributing.

 

What elements influence druggability?

The interaction of various parameters leads to druggability. Indicators that positively affect druggability include:

- Buriedness - Hydrophobicity - Pocket size

It has been proposed that the polar contact area has a deleterious impact.

For drug binding, polar interactions are still very important! (Salt bridges and H-bonds)

 

---- Summary ----

As of now you know all basics of all the laws of thermodynamics.

• Protein function

• CFactors influencing druggability

• Druggability

• etc..