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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...

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Related Experiment Video

Updated: Jun 19, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Computational design of ligand binding is not a solved problem.

Bettina Schreier1, Christian Stumpp, Silke Wiesner

  • 1The Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|October 17, 2009
PubMed
Summary

Computational protein design shows promise, but accurately predicting ligand binding remains a challenge. Structural analysis revealed designed proteins often lack stability, and predicted binding interactions were not confirmed experimentally.

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Area of Science:

  • Protein Engineering
  • Structural Biology
  • Computational Biology

Background:

  • Computational protein design has yielded novel proteins and enzymes.
  • The precision of predicted protein-ligand interactions requires detailed molecular investigation.

Purpose of the Study:

  • To structurally analyze designed receptors for their predicted protein-ligand interactions.
  • To assess the reliability of computational methods in designing functional ligand-binding proteins.

Main Methods:

  • Structural analysis of published periplasmic binding protein scaffold-based receptors.
  • Crystallography to determine the structure of a serotonin-binding protein.
  • Isothermal titration calorimetry, Circular Dichroism (CD), and Nuclear Magnetic Resonance (NMR) spectroscopy for binding characterization.

Main Results:

  • Most designed proteins exhibited instability and aggregation, hindering structural studies.
  • A designed serotonin-binding protein crystallized in an open conformation without bound ligand.
  • Experimental characterization (ITC, CD, NMR) failed to detect ligand binding for designed receptors, unlike wild-type controls.

Conclusions:

  • Computational prediction of side-chain conformations is accurate but does not guarantee functional ligand binding.
  • The computational design of ligand-binding proteins is an unsolved problem requiring further research and refinement.
  • Current computational design strategies need re-evaluation to ensure functional binding capabilities.