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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.
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Related Experiment Video

Updated: May 20, 2026

Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions

Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions

Published on: January 26, 2024

Peptide binding to the PDZ3 domain by conformational selection.

Sandra Steiner¹, Amedeo Caflisch

¹Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.

|July 4, 2012

Summary

PDZ domains bind to membrane proteins. Molecular dynamics simulations reveal that the PDZ3 domain binds ligands through conformational selection, not a simple lock-and-key mechanism, offering new insights into protein-protein interactions.

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Area of Science:

Protein structure and dynamics
Molecular recognition
Neuroscience

Background:

PDZ domains are crucial for protein localization by binding C-terminal segments of membrane proteins.
The precise mechanism of peptide binding to PDZ domains is not fully understood and varies between domains.
Previous studies suggested a lock-and-key mechanism for the PDZ3 domain of PSD-95 based on static crystal structures.

Purpose of the Study:

To investigate the peptide binding mechanism of the PDZ3 domain using advanced computational methods.
To elucidate the role of protein dynamics in PDZ domain-ligand interactions.
To determine if conformational selection plays a role in PDZ3 peptide binding.

Main Methods:

Explicit solvent molecular dynamics (MD) simulations totaling 1.3 μs.
Cut-based free energy profile calculations to identify energy barriers and basins.
Analysis of protein conformations and binding site dynamics.

Main Results:

The free energy landscape of apo PDZ3 revealed multiple native state basins differing in secondary structure orientation.
MD simulations showed that only a specific conformation with a narrow binding site aperture was populated.
Peptide binding to PDZ3 occurred through the selection of one of three specific conformations.

Conclusions:

The study provides dynamical insights that complement static crystallographic data for PDZ3.
Conformational selection is demonstrated as a viable mechanism for peptide binding by PDZ3.
This finding suggests conformational selection may be a general mechanism for peptide binding by PDZ domains.