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Conserved Binding Sites

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...

Conserved Binding Sites

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 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

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 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 the...

The Equilibrium Binding Constant and Binding Strength

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:

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Related Experiment Video

Updated: Jun 21, 2026

A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English

A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English

Published on: April 3, 2026

Computational fragment-based binding site identification by ligand competitive saturation.

Olgun Guvench¹, Alexander D MacKerell

¹Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, Baltimore, Maryland, USA.

Plos Computational Biology

|July 14, 2009

Summary

Site Identification by Ligand Competitive Saturation (SILCS) uses molecular dynamics to map protein fragment binding affinities. This computational method overcomes limitations of traditional techniques, improving fragment-based drug discovery.

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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

Published on: December 1, 2020

Area of Science:

Computational chemistry
Structural biology
Drug discovery

Background:

Fragment-based drug discovery (FBDD) using NMR and X-ray crystallography is effective but costly.
Existing computational FBDD methods struggle to accurately model protein flexibility and solvation effects, hindering reliable affinity ranking.

Purpose of the Study:

To introduce an advanced computational methodology for mapping protein fragment-binding affinities.
To overcome limitations in current computational FBDD approaches by incorporating protein flexibility and solvation.

Main Methods:

Developed an explicit solvent all-atom molecular dynamics methodology named Site Identification by Ligand Competitive Saturation (SILCS).
Used small molecules and water to map protein affinity for various chemical functionalities (hydrophobic, aromatic, H-bond donors/acceptors).
Generated three-dimensional probability maps of fragment binding (FragMaps) based on in silico free energy competition.

Main Results:

Applied SILCS to the oncoprotein BCL-6, generating two-fold symmetric FragMaps.
FragMaps accurately recapitulated known crystallographic binding modes of SMRT and BCOR peptides.
The method accounted for sequence/structure variations and protein side-chain mobility (BCL-6 His116).

Conclusions:

SILCS provides an atomic-level description of solvation and protein flexibility for fragment binding.
SILCS-generated FragMaps can guide small-molecule inhibitor design.
FragMaps can serve as scoring grids for high-throughput in silico docking.