A flexible docking scheme to explore the binding selectivity of PDZ domains

Area of Science:

• Computational chemistry
• Structural biology
• Molecular dynamics

Background:

• Protein binding site flexibility poses a significant challenge in molecular docking due to extensive conformational space.
• Accurate modeling of receptor flexibility is crucial for predicting binding poses and affinities.

Purpose of the Study:

• To develop and validate a novel flexible receptor docking scheme.
• To enhance the efficiency and accuracy of molecular docking by incorporating protein dynamics.

Main Methods:

• Utilized dihedral restrained replica exchange molecular dynamics (REMD) with normal modes from the Elastic Network Model (ENM) as restraints.
• Generated multiple receptor conformations (MRCs) by clustering low-energy REMD trajectories.
• Employed ROSETTALIGAND for docking ligands to the ensemble of MRCs.

Main Results:

• The method accurately predicted binding poses for postsynaptic density-95/Dlg/ZO-1 (PDZ) domains with an average ligand root mean square deviation of 0.36 Å.
• Successfully predicted binding poses and affinities for homologous and mutant PDZ structures with altered binding selectivity.
• Demonstrated the capability to generate an ensemble of MRCs for accurate protein-ligand interaction prediction.

Conclusions:

• The proposed flexible receptor docking scheme effectively addresses the challenge of protein binding site flexibility.
• The integration of ENM-biased REMD simulations provides an efficient way to explore relevant receptor conformations.
• This approach accurately predicts binding poses and specificities, offering a valuable tool for drug discovery and structural biology.