Conformational selection in silico: loop latching motions and ligand binding in enzymes

Area of Science:

• Computational biology
• Structural biology
• Drug discovery

Background:

• Ligand binding often induces significant protein conformational changes.
• Predicting these changes is vital for structure-based drug design.
• The "conformational selection" hypothesis suggests holo states exist transiently in apo proteins.

Purpose of the Study:

• To test the conformational selection hypothesis for loop latching events.
• To develop a computational method for predicting ligand-induced loop conformations.
• To assess the accuracy of predicted conformations in ligand docking.

Main Methods:

• Utilized replica exchange molecular dynamics and a loop prediction algorithm.
• Generated low-energy loop structures for up to 15-residue loops.
• Employed molecular docking to evaluate predicted conformations against known ligands.

Main Results:

• Successfully generated holo-like loop conformations within 2 Å RMSD for six test proteins.
• Predicted loop conformations improved ligand ranking compared to apo structures in 5/6 cases.
• Accurate ligand poses were achieved in 4/6 cases using predicted conformations.

Conclusions:

• The developed method can predict relevant loop conformations for ligand binding.
• The findings support the conformational selection mechanism in loop latching.
• Further refinement is needed for optimal performance compared to experimental holo structures.