Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 119, Issue 23, Pages 7030-7040Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.5b01625
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Funding
- Boehringer Ingelheim (BBSRC grant) [BB/I015922/1]
- BBSRC
- Biotechnology and Biological Sciences Research Council [1094769, BB/K016601/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/J015059/1, EP/J010588/1, EP/M022609/1] Funding Source: researchfish
- BBSRC [BB/K016601/1] Funding Source: UKRI
- EPSRC [EP/J010588/1, EP/M022609/1, EP/J015059/1] Funding Source: UKRI
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We present a method which uses DFT (quantum, QM) calculations to improve free energies of binding computed with classical fore fields (classical; MM). To overcome the incomplete overlap of configurational spaces between MM and QM, we use a hybrid Monte Carlo approach to generate quickly correct ensembles of structures of intermediate states between a MM and a QM/MM description, hence taking into account a great fraction, of the electronic polarization,of the quantum system, while being able to use thermodynamic integration to compute the free energy of transition between the MM and QM/MM. Then, we perform a final transition from QM/MM, to full QM using a one-step, free energy perturbation approach. By using QM/MM as a stepping stone toward the full QM description, we find very small convergence errors (<1 kJ/mol) in the transition to full QM. We apply this method to compute hydration free energies, and we obtain consistent improvements over the. MM values for all molecules we used in this study. This approach requires large-scale DFT calculations as the full QM systems involved the ligands and all waters in their simulation cells, so the linear-scaling DFT code ONETEP was used for these calculations.
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