Predicting accurate absolute binding energies in aqueous solution: thermodynamic considerations for electronic structure methods

TY - JOUR

T1 - Predicting accurate absolute binding energies in aqueous solution

T2 - thermodynamic considerations for electronic structure methods

AU - Jensen, Jan Halborg

PY - 2015/5/21

Y1 - 2015/5/21

N2 - Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic. In this paper I summarize some of the many factors that could easily contribute 1-3 kcal mol(-1) errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent.

AB - Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic. In this paper I summarize some of the many factors that could easily contribute 1-3 kcal mol(-1) errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent.

U2 - 10.1039/c5cp00628g

DO - 10.1039/c5cp00628g

M3 - Journal article

C2 - 25901455

SN - 1463-9076

VL - 17

SP - 12441

EP - 12451

JO - Physical chemistry chemical physics : PCCP

JF - Physical chemistry chemical physics : PCCP

IS - 19

ER -