Titel
The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations
Autor*in
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Abstract
Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating ΔAlow→high , remains to be the most challenging step within an indirect FES protocol. To improve calculations of ΔAlow→high , we must: (1) compare the performance of all FES methods currently available; and (2) compile and maintain datasets of ΔAlow→high calculated for a wide-variety of molecules so that future practitioners may replicate or improve upon the current state-of-the-art. Towards these two aims, we introduce a new dataset, “HiPen”, which tabulates ΔAMM→3obgas (the free energy associated with switching from an MM to an SCC−DFTB molecular description using the 3ob parameter set in gas phase), calculated for 22 drug-like small molecules. We compare the calculation of this value using free energy perturbation, Bennett’s acceptance ratio, Jarzynski’s equation, and Crooks’ equation. We also predict the reliability of each calculated ΔAMM→3obgas by evaluating several convergence criteria including sample size hysteresis, overlap statistics, and bias metric ( Π ). Within the total dataset, three distinct categories of molecules emerge: the “good” molecules, for which we can obtain converged ΔAMM→3obgas using Jarzynski’s equation; “bad” molecules which require Crooks’ equation to obtain a converged ΔAMM→3obgas ; and “ugly” molecules for which we cannot obtain reliably converged ΔAMM→3obgas with either Jarzynski’s or Crooks’ equations. We discuss, in depth, results from several example molecules in each of these categories and describe how dihedral discrepancies between levels of theory cause convergence failures even for these gas phase free energy simulations.
Stichwort
indirect free energy simulationsquantum mechanical molecular mechanical hybrid modelingfree energy perturbationnonequilibrium work simulationsBennett’s acceptance ratioJarzynski’s equationCrooks’ equation
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Molecules
Band
24
Ausgabe
4
ISSN
1420-3049
Erscheinungsdatum
2019
Publication
MDPI AG
Erscheinungsdatum
2019
Zugänglichkeit
Rechte
Rechteangabe
© 2019 by the authors
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