Inherent versus induced protein flexibility: Comparisons within and between apo and holo structures

Area of Science:

• Structural biology
• Computational drug design
• Protein dynamics

Background:

• Understanding protein flexibility upon ligand binding is critical for rational drug design.
• Existing studies analyze protein structures with (holo) and without (apo) ligands to assess conformational changes.

Purpose of the Study:

• To analyze protein flexibility changes induced by ligand binding.
• To compare backbone and side-chain flexibility in apo and holo states.
• To evaluate the impact of ligand binding on protein conformations for drug design.

Main Methods:

• Analysis of 305 proteins with 2369 holo and 1679 apo crystal structures.
• Comparison of inherent structural variations within apo and holo states.
• Quantification of conformational changes (RMSD, χ1 angles) between apo-holo pairs.

Main Results:

• Induced backbone flexibility upon ligand binding is minimal (RMSD < 0.5 Å).
• Ligand binding significantly influences side-chain (χ1 angles) conformations within the binding site.
• Side-chain conformational changes are often outside the range observed in apo states.

Conclusions:

• Protein backbone flexibility is less affected by ligand binding than side-chain flexibility.
• Observed side-chain flexibility is compatible with flexible docking methods that rigidify backbones.
• Findings provide insights into protein dynamics relevant for structure-based drug discovery.