AMMOS2: a web server for protein-ligand-water complexes refinement via molecular mechanics

Abstract

AMMOS2 is an interactive web server for efficient computational refinement of protein-small organic molecule complexes. The AMMOS2 protocol employs atomic-level energy minimization of a large number of experimental or modeled protein-ligand complexes. The web server is based on the previously developed standalone software AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening). AMMOS utilizes the physics-based force field AMMP sp4 and performs optimization of protein-ligand interactions at five levels of flexibility of the protein receptor. The new version 2 of AMMOS implemented in the AMMOS2 web server allows the users to include explicit water molecules and individual metal ions in the protein-ligand complexes during minimization. The web server provides comprehensive analysis of computed energies and interactive visualization of refined protein-ligand complexes. The ligands are ranked by the minimized binding energies allowing the users to perform additional analysis for drug discovery or chemical biology projects. The web server has been extensively tested on 21 diverse protein-ligand complexes. AMMOS2 minimization shows consistent improvement over the initial complex structures in terms of minimized protein-ligand binding energies and water positions optimization. The AMMOS2 web server is freely available without any registration requirement at the URL: http://drugmod.rpbs.univ-paris-diderot.fr/ammosHome.php.

Figure 1.

Flowchart of AMMOS2 web server workflow depicting interface organization, input, validation, execution and output layers of the server.

Figure 2.

Protein–ligand interaction energies (in kcal/mol) before and after minimization with AMMOS2 for the best docking pose with a different number of water molecules in the binding pocket for trypsin (A), cAMP-dependent protein kinase (B) and neuraminidase (C). C0 notes the energy of the docked complex before minimization, C1 to C5 correspond to the five cases of protein flexibility. The PDB ID of the proteins are given.

Figure 3.

Binding site of the catalytic subunit of cAMP-dependent protein kinase in a complex with isoquinolinesulfonyl inhibitor H8. The X-ray structure of the protein and the ligand H8 are shown in cyan cartoon and cyan sticks, respectively; water molecules are shown in cyan dots (PDB ID 1YDS). The ligand H8 and five selected water molecules close to the ligand after AMMOS2 case 1 minimization are shown in salmon. The ligand H8 and all water molecules within 6 Å around the ligand after AMMOS2 case 1 minimization are shown in magenta.