Artículo

Arcon, J.P.; Defelipe, L.A.; Modenutti, C.P.; López, E.D.; Alvarez-Garcia, D.; Barril, X.; Turjanski, A.G.; Martí, M.A. "Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions" (2017) Journal of Chemical Information and Modeling. 57(4):846-863
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Abstract:

One of the most important biological processes at the molecular level is the formation of protein-ligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Because of its low cost relative to its experimental sibling, molecular dynamics (MD) simulations in the presence of different solvent probes mimicking specific types of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots. However, a systematic comparison of different probes and their real predictive power from a quantitative and thermodynamic point of view is still missing. In the present work, we have performed MD simulations of 18 different proteins in pure water as well as water mixtures of ethanol, acetamide, acetonitrile and methylammonium acetate, leading to a total of 5.4 μs simulation time. For each system, we determined the corresponding solvent sites, defined as space regions adjacent to the protein surface where the probability of finding a probe atom is higher than that in the bulk solvent. Finally, we compared the identified solvent sites with 121 different protein-ligand complexes and used them to perform molecular docking and ligand binding free energy estimates. Our results show that combining solely water and ethanol sites allows sampling over 70% of all possible protein-ligand interactions, especially those that coincide with ligand-based pharmacophoric points. Most important, we also show how the solvent sites can be used to significantly improve ligand docking in terms of both accuracy and precision, and that accurate predictions of ligand binding free energies, along with relative ranking of ligand affinity, can be performed. © 2017 American Chemical Society.

Registro:

Documento: Artículo
Título:Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions
Autor:Arcon, J.P.; Defelipe, L.A.; Modenutti, C.P.; López, E.D.; Alvarez-Garcia, D.; Barril, X.; Turjanski, A.G.; Martí, M.A.
Filiación:Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Ciudad de Buenos Aires, C1428EHA, Argentina
Discngine, 33 rue du Fauburg Saint-Antoine, Paris, 75011, France
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Spain
Palabras clave:Binding sites; Complexation; Ethanol; Free energy; Ligands; Molecular dynamics; Probes; Proteins; Solvents; Accuracy and precision; Accurate prediction; Binding free energy; Biological process; Molecular dynamics simulations; Protein-binding sites; Protein-ligand complexes; Protein-ligand interactions; Binding energy; ligand; protein; protein binding; solvent; water; chemical phenomena; chemistry; metabolism; molecular docking; molecular dynamics; protein conformation; thermodynamics; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Proteins; Solvents; Thermodynamics; Water
Año:2017
Volumen:57
Número:4
Página de inicio:846
Página de fin:863
DOI: http://dx.doi.org/10.1021/acs.jcim.6b00678
Título revista:Journal of Chemical Information and Modeling
Título revista abreviado:J. Chem. Inf. Model.
ISSN:15499596
CODEN:JCISD
CAS:protein, 67254-75-5; water, 7732-18-5; Ligands; Proteins; Solvents; Water
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15499596_v57_n4_p846_Arcon

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Citas:

---------- APA ----------
Arcon, J.P., Defelipe, L.A., Modenutti, C.P., López, E.D., Alvarez-Garcia, D., Barril, X., Turjanski, A.G.,..., Martí, M.A. (2017) . Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions. Journal of Chemical Information and Modeling, 57(4), 846-863.
http://dx.doi.org/10.1021/acs.jcim.6b00678
---------- CHICAGO ----------
Arcon, J.P., Defelipe, L.A., Modenutti, C.P., López, E.D., Alvarez-Garcia, D., Barril, X., et al. "Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions" . Journal of Chemical Information and Modeling 57, no. 4 (2017) : 846-863.
http://dx.doi.org/10.1021/acs.jcim.6b00678
---------- MLA ----------
Arcon, J.P., Defelipe, L.A., Modenutti, C.P., López, E.D., Alvarez-Garcia, D., Barril, X., et al. "Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions" . Journal of Chemical Information and Modeling, vol. 57, no. 4, 2017, pp. 846-863.
http://dx.doi.org/10.1021/acs.jcim.6b00678
---------- VANCOUVER ----------
Arcon, J.P., Defelipe, L.A., Modenutti, C.P., López, E.D., Alvarez-Garcia, D., Barril, X., et al. Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions. J. Chem. Inf. Model. 2017;57(4):846-863.
http://dx.doi.org/10.1021/acs.jcim.6b00678