Exploring protein flexibility: incorporating structural ensembles from crystal structures and simulation into virtual...

Area of Science:

• Structural Biology
• Computational Chemistry
• Drug Discovery

Background:

• Proteins exhibit conformational plasticity, adapting structure in response to modifications, ligands, and protein interactions, which is crucial for biological functions.
• Understanding and sampling protein conformational landscapes, particularly ligand binding site geometry, is essential for effective virtual screening in drug discovery.

Purpose of the Study:

• To evaluate the ability of molecular dynamics (MD), replica exchange molecular dynamics (REMD), and crystal structure libraries to sample protein conformational space.
• To assess how well these sampled conformations, when used in ensemble docking, improve virtual screening enrichment and diversity for identifying active compounds.

Main Methods:

• Utilized molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulations to explore protein conformational landscapes.
• Generated ensembles of protein structures from simulations and crystal-ligand complexes.
• Employed hierarchical clustering of binding site shapes to select four representative structures per ensemble for docking studies.

Main Results:

• Replica exchange molecular dynamics (REMD) showed a slight improvement in structural sampling compared to standard molecular dynamics (MD) and crystal structures.
• Despite enhanced sampling from simulations, this did not directly translate to superior docking performance.
• Ensemble docking strategies significantly improved both enrichment and diversity; ensembles derived from crystal structures outperformed those from simulations.

Conclusions:

• Protein conformational plasticity is significant and influences ligand binding site accessibility.
• Ensemble docking is a valuable strategy for enhancing virtual screening efficiency.
• Crystal structure-derived ensembles are more effective for virtual screening than simulation-derived ensembles in the tested cases.