TY - JOUR

T1 - Calculations of Solvation Free Energy through Energy Reweighting from Molecular Mechanics to Quantum Mechanics

AU - Jia, Xiangyu

AU - Wang, Meiting

AU - Shao, Yihan

AU - König, Gerhard

AU - Brooks, Bernard R.

AU - Zhang, John Z.H.

AU - Mei, Ye

N1 - Funding Information:
We thank Dr. Stefan Boresch and Dr. Michael Shirts for helpful discussions. This work is supported by the National Natural Science Foundation of China (Grant Nos. 21173082 and 21433004) and the Large Instruments Open Foundation of East China Normal University. We also thank the Supercomputer Center of East China Normal University for CPU time support.

PY - 2016/2/9

Y1 - 2016/2/9

N2 - In this work, the solvation free energies of 20 organic molecules from the 4th Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL4) have been calculated. The sampling of phase space is carried out at a molecular mechanical level, and the associated free energy changes are estimated using the Bennett Acceptance Ratio (BAR). Then the quantum mechanical (QM) corrections are computed through the indirect Non-Boltzmann Bennett's acceptance ratio (NBB) or the thermodynamics perturbation (TP) method. We show that BAR+TP gives a minimum analytic variance for the calculated solvation free energy at the Gaussian limit and performs slightly better than NBB in practice. Furthermore, the expense of the QM calculations in TP is only half of that in NBB. We also show that defining the biasing potential as the difference of the solute-solvent interaction energy, instead of the total energy, can converge the calculated solvation free energies much faster but possibly to different values. Based on the experimental solvation free energies which have been published before, it is discovered in this study that BLYP yields better results than MP2 and some other later functionals such as B3LYP, M06-2X, and ωB97X-D.

AB - In this work, the solvation free energies of 20 organic molecules from the 4th Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL4) have been calculated. The sampling of phase space is carried out at a molecular mechanical level, and the associated free energy changes are estimated using the Bennett Acceptance Ratio (BAR). Then the quantum mechanical (QM) corrections are computed through the indirect Non-Boltzmann Bennett's acceptance ratio (NBB) or the thermodynamics perturbation (TP) method. We show that BAR+TP gives a minimum analytic variance for the calculated solvation free energy at the Gaussian limit and performs slightly better than NBB in practice. Furthermore, the expense of the QM calculations in TP is only half of that in NBB. We also show that defining the biasing potential as the difference of the solute-solvent interaction energy, instead of the total energy, can converge the calculated solvation free energies much faster but possibly to different values. Based on the experimental solvation free energies which have been published before, it is discovered in this study that BLYP yields better results than MP2 and some other later functionals such as B3LYP, M06-2X, and ωB97X-D.

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U2 - 10.1021/acs.jctc.5b00920

DO - 10.1021/acs.jctc.5b00920

M3 - Article

C2 - 26731197

AN - SCOPUS:84957967059

VL - 12

SP - 499

EP - 511

JO - Journal of Chemical Theory and Computation

JF - Journal of Chemical Theory and Computation

SN - 1549-9618

IS - 2

ER -