Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Simulating protein-ligand interactions is computationally intensive due to complex energy landscapes.
• Accurate protein-ligand docking is crucial for drug discovery and development.

Purpose of the Study:

• To introduce interactive molecular dynamics in virtual reality (iMD-VR) as an efficient and cost-effective strategy for flexible protein-ligand docking.
• To evaluate the accuracy and speed of iMD-VR for recreating crystallographic binding poses.

Main Methods:

• Development of an experimental protocol for iMD-VR guided ligand docking and unbinding.
• Application of iMD-VR to trypsin, neuraminidase, and HIV-1 protease systems.
• Comparison of binding pose recovery by iMD-VR experts and novices against crystallographic data.

Main Results:

• iMD-VR enabled experts to recreate crystallographic poses for trypsin, neuraminidase, and HIV-1 protease within 5-10 minutes.
• Novices, after brief training, achieved similar timescales for generating unbinding/rebinding pathways.
• The majority of users recovered binding poses within 2.15 Å RMSD of the experimental structures.

Conclusions:

• iMD-VR provides sufficient user control for atomic manipulations in flexible ligand docking.
• This method offers a novel approach for simulating drug docking and generating binding hypotheses.
• iMD-VR significantly reduces computational cost and time for protein-ligand docking studies.