High quality ligand-binding-site structure in its holo conformation is a valuable receptor structure that can be useful in drug design through structure-based virtual screening. Available apo structures (both experimentally and computationally determined) tend to have low quality ligand-binding-site regions that are not suitable for ligand docking or structural analysis. This is because the ligand-binding-site region of a protein is flexible and undergoes conformational changes during binding. In this work, we present a ligand-binding-site structure refinement protocol to generate high quality holo conformations from apo structures or homology models. We use physics-based molecular dynamics (MD) simulations with restraints derived from predicted binding site templates. Benchmark validation for large datasets from various sources, including the Astex list and DUD-E database, shows great results. The ligand-binding-site structures are consistently refined from easy, medium, to difficult targets. Ligand binding modes from docking of native ligands to initial unrefined and refined structures also show consistent improvements after refinement. In order to make our refinement protocol easily available for general users, we develop <i>Binding Site Refiner</i>, a new CHARMM-GUI module that provides predicted binding site templates and restraint potentials for a query structure (apo structure or homology model) submitted by a user. This module will provide appropriate simulation input files to help users run their ligand-binding-site structure refinement MD simulations with restraints derived from predicted binding site templates. We expect that <i>Binding Site Refiner</i> will be a useful tool to the structural biology and pharmacology community in obtaining reliable protein structures for virtual screening and structural analysis.

Ligand-binding-site structure refinement

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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