MDO: A Computational Protocol for Prediction of Flexible Enzyme-ligand Binding Mode

Abstract

Aim: Developing a method for use in computer aided drug design Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved. Objective: Accurate prediction of enzyme-ligand binding mode conformation. Method: A new computational protocol, MDO, is proposed for finding the structure of ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures. Results: The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. Conclusion: The MDO protocol provides high quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structure-based drug design.

Quantum Mechanics-Based Fast and Reliable Prediction of Binding Pose Structures

“…The binding pose prediction consists of three steps: (1) generation of initial ligand conformations by global minimum energy, (2) generation of ligand conformations by molecular docking, (3) ranking the binding modes by ONIOM single-point energy, and optimizing the top 10 binding modes by ONIOM optimization. The ONIOM approach is chosen for the geometry optimization due to its exceptional fidelity in replicating the experimental structures of protein–ligand binding poses. − The workflow is shown in Figure , and the operation details are described in the following text.…”

“…The alternative is the computational scheme using docking tools. Protocols, such as DOX, SAMP, − COV_DOX, and MDO, combining docking with DFTB, are often used to predict the three-dimensional (3D) binding modes of proteins and ligands without X-ray determination for the complexes. These protocols are used to find the correct binding modes through conformational search using molecular docking and geometry optimizations with the ONIOM method …”