Interactions in native binding sites cause a large change in protein dynamics

Area of Science:

• Biophysics
• Computational Biology
• Structural Biology

Background:

• Cellular functions rely on molecular interactions that modulate protein activity.
• Protein conformational changes are key to regulating these activities.
• Understanding how molecular interactions affect protein conformation is crucial for drug discovery and biological research.

Purpose of the Study:

• To investigate if interactions at functional sites induce substantial changes in protein conformational distributions.
• To develop and validate a computational method for predicting protein functional sites based on interaction-induced conformational changes.

Main Methods:

• Dynamics Perturbation Analysis (DPA) was employed to calculate the allosteric potential D(x) at various protein surface points.
• D(x) quantifies the change in protein conformational distribution upon molecular interaction.
• A coarse-grained model of protein vibrations was used to compute D(x) for hundreds of protein structures.

Main Results:

• Ligand-binding sites consistently exhibited elevated D(x) values, indicating significant conformational changes.
• For 95% of proteins studied, the probability of achieving such high D(x) values randomly was less than 10^-3.
• A DPA-based method accurately predicted ligand-binding-site residues, outperforming a cleft analysis method.

Conclusions:

• Interactions at small-molecule binding sites induce large alterations in protein conformational distributions.
• DPA is a valuable tool for large-scale prediction of functional sites in proteins.
• Evolution appears to favor proteins whose activities are readily regulated by molecular interactions.