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Ligand Binding Sites

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 Sites

Ligand Binding Sites

Ligand Binding and Linkage

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...

Ligand Binding and Linkage

Ligand Binding and Linkage

Cooperative Allosteric Transitions

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...

Cooperative Allosteric Transitions

Cooperative Allosteric Transitions

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Related Experiment Video

Updated: Mar 14, 2026

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

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

Detecting the native ligand orientation by interfacial rigidity: SiteInterlock.

Sebastian Raschka¹, Joseph Bemister-Buffington¹, Leslie A Kuhn^1,2

¹Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, 48824, USA.

|October 5, 2016

Summary

This summary is machine-generated.

Protein-ligand binding rigidifies interfaces, a key physical attribute for biological activity. The SiteInterlock method uses rigidity theory to identify native binding modes, outperforming other scoring functions.

Keywords:

ProFlex binding determinants binding mode prediction coupled interactions docking flexibility interface features ligand stabilization of proteins protein stability scoring functions

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Published on: July 8, 2025

Area of Science:

Biophysics
Computational Biology
Structural Biology

Background:

Protein-ligand interactions are crucial for biological activity and drug design.
Traditional methods for predicting these interactions include physics-based, empirical, and knowledge-based potentials.
A fundamental challenge lies in understanding the physical attributes of these interfaces.

Purpose of the Study:

To test the hypothesis that protein-ligand binding causes detectable rigidification of the interface.
To introduce and evaluate the SiteInterlock approach for measuring interfacial rigidity.
To assess the performance of rigidity as a predictor of native protein-ligand binding modes.

Main Methods:

Utilized rigidity theory to develop the SiteInterlock approach.
Measured the relative interfacial rigidity of various ligand orientations and conformations for protein complexes.
Compared SiteInterlock's performance against five other scoring functions.

Main Results:

SiteInterlock identified near-native binding modes as the most rigid in most cases.
Interfacial rigidification of both protein and ligand were important indicators of native binding.
The method showed robust performance, especially when the ligand-free protein conformation was available.
SiteInterlock's rigidity measure captures cooperative binding interactions, offering novel insights.

Conclusions:

Interfacial rigidity is a significant characteristic of native protein-ligand complexes.
SiteInterlock provides a competitive and novel approach for predicting protein-ligand interactions.
The method excels at enhancing native complex prediction by effectively ruling out inaccurate poses.