Dataset Information

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

ABSTRACT: We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the FreeSolv database (621 out of 642). The force field parameters were obtained with the program cgenff (v2.5.1), which derives missing parameters from the CHARMM general force field (CGenFF v4.6). A long-range correction for the Lennard-Jones interactions was added to all computed solvation free energies. The mean absolute error compared to the experimental data is 1.12 kcal/mol. Our results allow a detailed comparison between the AMBER and CHARMM general force fields and provide a more in-depth understanding of the capabilities and limitations of the CGenFF small molecule parameters.

SUBMITTER: Karwounopoulos J

PROVIDER: S-EPMC10500982 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

Karwounopoulos Johannes J Kaupang Åsmund Å Wieder Marcus M Boresch Stefan S

Journal of chemical theory and computation 20230824 17

We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the F ...[more]

PMID: 37616333

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Project description:A grand challenge of computational biophysics is accurate prediction of interactions between molecules. Molecular dynamics (MD) simulations have recently gained much interest as a tool to directly compute rigorous intermolecular binding affinities. The choice of a fixed point-charge or polarizable multipole force field used in MD is a topic of ongoing discussion. To compare alternative methods, we participated in the SAMPL7 and SAMPL8 Gibb octaacid host-guest challenges to assess the Atomic Multipole Optimized Energetics for Biomolecular Applications (AMOEBA) polarizable multipole force field. Advantages of AMOEBA over fixed charge models include improved representation of molecular electrostatic potentials and better description of water occupying the unligated host cavity. Prospective predictions for 26 host-guest systems exhibit a mean unsigned error vs experiment of 0.848 kcal/mol across all absolute binding free energies, demonstrating excellent agreement between computational and experimental results. In addition, we explore two topics related to the inclusion of ions in MD simulations: use of a neutral co-alchemical protocol and the effect of salt concentration on binding affinity. Use of the co-alchemical method minimally affects computed energies, but salt concentration significantly perturbs our binding results. Higher salt concentration strengthens binding through classical charge screening. In particular, added Na+ ions screen negatively charged carboxylate groups near the binding cavity, thereby diminishing repulsive coulomb interactions with negatively charged guests. Overall, the AMOEBA results demonstrate the accuracy available through a force field providing a detailed energetic description of the four octaacid hosts and 13 charged organic guests. Use of the AMOEBA polarizable atomic multipole force field in conjunction with an alchemical free energy protocol can achieve chemical accuracy in application to realistic molecular systems.

Dataset Information

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

Publications

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

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