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 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.
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Juan Pablo
0000-0003-3350-1576
JP
Arcon
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Lucas A
0000-0001-7859-7300
LA
Defelipe
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Carlos P
CP
Modenutti
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Elias D
ED
López
Discngine , 33 rue du Fauburg Saint-Antoine, 75011 Paris, France.
Daniel
0000-0002-2867-5005
D
Alvarez-Garcia
Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmàcia, Universitat de Barcelona , Av. Joan XXIII s/n, 08028 Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA) , Passeig Lluís Companys 23, 08010 Barcelona, Spain.
Xavier
0000-0002-0281-1347
X
Barril
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Adrián G
AG
Turjanski
Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina.
Marcelo A
0000-0002-7911-9340
MA
Martí
D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D008024:Ligands; D011506:Proteins; D012997:Solvents; D014867:Water