Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Simulations for Protein–Ligand Complexes: Free Energies of Binding of Water Molecules in Influenza Neuraminidase
| العنوان: | Combined Quantum Mechanics/Molecular Mechanics (QM/MM) Simulations for Protein–Ligand Complexes: Free Energies of Binding of Water Molecules in Influenza Neuraminidase |
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| المؤلفون: | Katherine E. Shaw, Christopher J. Woods, Adrian J. Mulholland |
| المصدر: | The Journal of Physical Chemistry B. 119:997-1001 |
| بيانات النشر: | American Chemical Society (ACS), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Models, Molecular, Monte Carlo method, Neuraminidase, Ligands, Molecular mechanics, QM/MM, Computational chemistry, Quantum mechanics, Materials Chemistry, Bound water, Molecule, Physical and Theoretical Chemistry, biology, Chemistry, Water, Orthomyxoviridae, Surfaces, Coatings and Films, Crystallography, biology.protein, Quantum Theory, Thermodynamics, Free energies, Monte Carlo Method, Protein Binding, Protein ligand |
| الوصف: | The applicability of combined quantum mechanics/molecular mechanics (QM/MM) methods for the calculation of absolute binding free energies of conserved water molecules in protein/ligand complexes is demonstrated. Here, we apply QM/MM Monte Carlo simulations to investigate binding of water molecules to influenza neuraminidase. We investigate five different complexes, including those with the drugs oseltamivir and peramivir. We investigate water molecules in two different environments, one more hydrophobic and one hydrophilic. We calculate the free-energy change for perturbation of a QM to MM representation of the bound water molecule. The calculations are performed at the BLYP/aVDZ (QM) and TIP4P (MM) levels of theory, which we have previously demonstrated to be consistent with one another for QM/MM modeling. The results show that the QM to MM perturbation is significant in both environments (greater than 1 kcal mol(-1)) and larger in the more hydrophilic site. Comparison with the same perturbation in bulk water shows that this makes a contribution to binding. The results quantify how electronic polarization differences in different environments affect binding affinity and also demonstrate that extensive, converged QM/MM free-energy simulations, with good levels of QM theory, are now practical for protein/ligand complexes. |
| تدمد: | 1520-5207 1520-6106 |
| DOI: | 10.1021/jp506413j |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d07562826b43ea74092ae967193e6ed9 https://doi.org/10.1021/jp506413j |
| رقم الانضمام: | edsair.doi.dedup.....d07562826b43ea74092ae967193e6ed9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15205207 15206106 |
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| DOI: | 10.1021/jp506413j |