Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions
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 it...
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15499596_v57_n4_p846_Arcon http://hdl.handle.net/20.500.12110/paper_15499596_v57_n4_p846_Arcon |
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paper:paper_15499596_v57_n4_p846_Arcon2023-06-08T16:21:22Z Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions Defelipe, Lucas Alfredo Turjanski, Adrián Gustavo 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 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. Fil:Defelipe, L.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15499596_v57_n4_p846_Arcon http://hdl.handle.net/20.500.12110/paper_15499596_v57_n4_p846_Arcon |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Defelipe, Lucas Alfredo Turjanski, Adrián Gustavo Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| topic_facet |
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 |
| description |
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. |
| author |
Defelipe, Lucas Alfredo Turjanski, Adrián Gustavo |
| author_facet |
Defelipe, Lucas Alfredo Turjanski, Adrián Gustavo |
| author_sort |
Defelipe, Lucas Alfredo |
| title |
Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| title_short |
Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| title_full |
Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| title_fullStr |
Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| title_full_unstemmed |
Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions |
| title_sort |
molecular dynamics in mixed solvents reveals protein-ligand interactions, improves docking, and allows accurate binding free energy predictions |
| publishDate |
2017 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15499596_v57_n4_p846_Arcon http://hdl.handle.net/20.500.12110/paper_15499596_v57_n4_p846_Arcon |
| work_keys_str_mv |
AT defelipelucasalfredo moleculardynamicsinmixedsolventsrevealsproteinligandinteractionsimprovesdockingandallowsaccuratebindingfreeenergypredictions AT turjanskiadriangustavo moleculardynamicsinmixedsolventsrevealsproteinligandinteractionsimprovesdockingandallowsaccuratebindingfreeenergypredictions |
| _version_ |
1768544244313620480 |