Accurate simulations of free energy, and thus the constituent entropy and enthalpy contributions, are essential to understand many entropy/enthalpy compensation phenomena involved in ligand binding, molecular recognition, functional material self-organization, and chemical reactions. Although interpretation of entropy and enthalpy contributions in the condensed phase have been possible for some time with efficient force field models, recent advances in electronic structure efficiency and accuracy have made it recently possible to also evaluate these trends fully from first principles. Even as differences or agreement for reaction enthalpies are relatively well-understood, it is not known the extent to which different levels of theories, ranging from classical molecular mechanics, semi-empirical quantum mechanics, to <i>ab initio</i> quantum mechanics, are likely to produce different free energies or constituent entropies and enthalpies for a certain chemical process. In this study, we benchmark how this range of methods give different descriptions on molecular complexation for representative systems, including the formation of water dimer, DNA base pairs, peptide intramolecular hydrogen bonds, and crown ether metal complexes. The entropies are assessed by normal mode analysis, potential of mean force, and two-phase thermodynamics. This work may instruct the development of methods for accurate computation of energy decomposition, help identify when classical molecular dynamics sampling does and does not provide a suitable representation of a system’s degrees of freedom, and enhance the understanding of fundamental chemical transformations.

Assessment of quantum mechanical and molecular mechanical methods on free energy decomposition of small molecule complexation

256th National Meeting (2018)

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