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Molecular modeling for drug design
AMMOS2 (Automatic Molecular Mechanics Optimization for in silico Screening) employs an automatic procedure for energy minimization of protein-ligands complexes.
AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening)[Pencheva 2008] is a software platform that employs an automatic procedure for energy minimization of protein-ligands complexes via the website AMMOS2 and of small chemical compounds via the website AMMOS. AMMOS offers valuable solutions to assist structure-based in silico screening experiments or ligand-based projects. It makes use of molecular mechanics concepts and is based on the program AMMP [Harrison 1997, Weber 1998], available under GNU license. AMMOS has been developed by the QSAR and Molecular Modelling Dep., IBBE, BAS and the MTi lab, INSERM U973 – University Paris Diderot. Please, cite:Pencheva T, Lagorce D, Pajeva I, Villoutreix B, Miteva MA., AMMOS: Automated Molecular Mechanics Optimization Tool for in silico Screening, BMC Bioinformatics, 2008, 9:438Jereva D, Pencheva T, Lagorce D, Desvillechabrol D, Pajeva I, Miteva MA. Post-docking optimization of protein-ligand interactions involving water molecules. Asian J Physics. 2014; 23: 745-56 You may direct questions related to AMMOS to:Maria A. MitevaMTi, INSERM U973 - University Paris DiderotE-mail: firstname.lastname@example.org
AMMOS2 performs energy minimization of protein-ligand complexes and can be applied on a large number of experimental or modeled protein-ligand complex structures, i.e. pre-generated via a user-chosen docking programs or e.g. via the MTiOpenScreen web server. The molecular mechanics minimization of AMMOS2 is based on the AMMP force field sp4 [Bagossi 1999] developed by use of the UFF potential set [ Rappe et al. 1992]. Intermolecular interactions include Electrostatic and van der Waals interactions. The minimization is realized by performing 2×500 conjugate gradient iterations. AMMOS2 requires as input a protein file in pdb format and docked small ligands in mol2 format. The translation of small molecule and protein files format in a specific ammp format is executed by the PREAMMP program, which is a part of the AMMP package and the AMMOS2 web service.protein flexibility AMMOS2 allows optimization of proteins - small organic molecules interaction at five levels of flexibility of the protein receptor, while ligands are always flexible:Allowed to be flexible:
The entire procedure of AMMOS2 is shown in the following scheme:
AMMOS2 requires two input files: the protein in pdb format and a compound collection containing the pre-docked ligands in mol2 format. Before to proceed to AMMOS2 use, please consider following requirements:Protein and ligand namesPlease, ensure that the protein and ligand file names do not contain any spaces.The protein PDB file name should finish by .pdbThe ligand MOL2 file name should finish by .mol2The field of charges in the mol2 file should be provided or assigned to 0.0000.How to prepare the proteinAMMOS2 requires a protein in pdb format with no more than 1000 residues. It is expected the protein to be properly protonated by the user. The hydrogen atom names should correspond to atom names assigned by CHIMERA.The format of HETATM field of the input PDB should be like:"HETATM 4976 O HOH A2500 -33.154 84.346 62.465 1.00 68.42 O""HETATM 3234 CA CA A 224 37.739 25.336 34.972 1.00 0.00 Ca" For FE2 and FE3, please use residue name FE2 or FE3. and not like:"HETATM15147 O HOH A2058 -30.531 68.972 12.744 1.00 34.99 O""HETATM 3234 CA CA3 A 224 37.739 25.336 34.972 1.00 0.00 Ca"How to prepare the ligandsAMMOS2 requires a compound collection containing the pre-docked ligands in mol2 format. A collection of up to 300 ligands is acceptable for the Cases 1, 2 and 5, while for the Cases 3 and 4, collections of up to 2000 ligands might be introduced. For all Cases, the maximum number of atoms in the ligand should not exceed the number of 300, including hydrogens. Ligand hydrogens can be provided by the user or added by AMMOS2.Radius of the binding siteThe user-defined radius of a sphere around the ligand atoms for Cases 3 and 4 should be between 4 and 8 Å.How to run
Your results will be kept during 2 weeks after the job terminationPlease, keep your jobID.After the job submission the page will be refreshed automatically every 30 seconds. After the job termination you can download the results as a tar archive. The tar file contains:
Ammos2 web server has been rigorously benchmarked for the performance of our implementation of the Ammos software. Ammos2 molecular mechanics minimization performance has been validated against 21 diverse and extensively checked protein-ligand complexes from the PDB (CCDC/Astex Test Set). We selected several classes of important protein targets (nuclear receptors, kinases, serine proteases, ribonucleases among others) with available high quality crystal structures manually selected from the Astex test dataset. The ability of Ammos2 to improve the protein-ligand interaction predictions was validated after molecular docking of co-crystallized ligands by using AutoDock4. The molecular mechanics optimization of docked protein-ligand complexes was performed by Ammos2 for five different cases of protein flexibility, in presence or absence of explicit water molecules located in the binding pocket or in the whole protein. The impact of considering water molecules during the minimization on the ligand binding modes and binding energies was assessed. Two examples are shown here for CAMP-dependent protein kinase (PDB ID: 1yds, 1ydr, 1ydt) and trypsin (PDB ID: 1mtw, 1mts, and 1ql7). Including protein flexibility during the minimization with Ammos2 optimized the interactions in the complexes, resulting in more favorable interaction energies. Adding several water molecules in the binding site also improved the protein-ligand interaction energies and optimized the positions of waters mediating the ligand-protein interactions.Figure 1. Binding energies of protein-ligand complexes minimized by Ammos2 in absence of water (0 H2O), or in presence of selected 4 or 5 water molecules in the binding site, on in presence of all X-ray water molecules within 6 Å of the ligand.Figure 2. The X-ray structure of trypsin (PDB ID 1MTS) and its co-crystallized ligand are shown in cyan and green, respectively; water molecules are shown as dots. The protein and ligand minimized by Ammos2 Case 3 with present waters (shown as red spheres) within 6 Å of the ligand are shown in pink.
Bagossi P., G. Zahuczky, J. Tözsér, I. Weber, R. Harrison. Improved Parameters for Generating Partial Charges: Correlation with Observed Dipole Moments, Journal of Molecular Modeling, 1999, 5, 143-152Harrison R., C. Reed, I. Weber. Analysis of Comparative Modeling Predictions for CASP2 Targets 1, 3, 9, and 17. Proteins: Structure, Function, and Genetics, 1997, Suppl. 1, 68-73Jereva D., T. Pencheva, D. Lagorce, D. Desvillechabrol, I. Pajeva, M. Miteva, Post-docking Optimization of Protein-Ligand Interactions Involving Water Molecules, Asian Journal of Physics, 2014, 23, 745-756Pencheva T., D. Lagorce, I. Pajeva, Br. Villoutreix, M. Miteva, AMMOS: Automated Molecular Mechanics Optimization Tool for in silico Screening, BMC Bioinformatics, 2008, 9:438Pencheva T., D. Lagorce, I. Pajeva, B. O. Villoutreix, M. A. Miteva, AMMOS Software: Method and Application, Methods Mol Biol, Computational Drug Discovery and Design, R. Baron (Ed.), Humana Press, 2012, 819, 127-141Pencheva T., O. S. Soumana, I. Pajeva, M. A. Miteva, Post-docking Virtual Screening of Diverse Binding Pockets: Comparative Study Using DOCK, AMMOS, X-Score and FRED Scoring Functions, Eur J Med Chem, 2010, 45, 2622-2628Rappé AK, Casewit CJ, Colwell KS, Goddard WA, III, Skiff WM. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J Am Chem Soc, 1992, 114, 10024–10035Weber I., R. Harrison. Molecular Mechanics Calculations on Protein–Ligand Complexes. Perspectives in Drug Discovery and Design, 1998, 9/10/11, 115-127
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