The core of the LigParGen server is the internal use of the BOSS (32 (link)) software to assign the bonded and van der Waals parameters by analogy to the existing atom types in the latest OPLS-AA force field (4 (link)). Subsequently a semiempirical AM1 (9 (link)) calculation is performed to calculate and assign the charges. The server can, as directed by the user, utilize one of two CM1A-derived charge models as described briefly below. For further information about technical details and comparisons, please read the original papers (9 (link),16 (link)).
In general, quantum mechanics population analysis methods distribute the total electron density of a molecule into partial charges centered on each atom of the molecule. As partial charges are not observables, there are different ways to partition the electron density. The CM1A method uses the Mulliken population analysis from the electron density obtained by the AM1 method from the ligand geometry. Mulliken charges for an atom A are computed using the following equation: where is the partial Mulliken charge, is the nuclear charge of the atom A and is the electron density assigned to atom A as described by the equation:
where N is the total number of electrons in the molecule, is the molecular orbital coefficient for the atomic orbital and is the QM overlap integral. This electron density definition is based on the linear combination of atomic orbital–molecular orbital (LCAO–MO) method where the molecular electronic distribution per each molecular orbital is defined each as a linear combination of atomic orbitals (n).
The CM1A charges are then computed using a multilinear transformation of the Mulliken charges based in the computed bond orders to improve the molecular dipole moment using empirical parameters. Then, for neutral molecules, the 1.14*CM1A model scales the charges by a factor 1.14, which was fitted to improve the agreement of the HFEs to the experimental values (16 (link)). If the total charge of the molecule is not zero, partial charges are not scaled. It should be noted that, as in all quantum mechanics based charges, the CM1A charges can have some variations due to the molecular geometry. The typical variations observed in our tests are in the 0.03–0.05 e range, with a few cases involving intramolecular hydrogen bonds reaching 0.1e.
A later evaluation of HFEs for a set of 426 organic molecules showed that some moieties such as phenyl rings, aldehydes or ketones are not well parameterized by the 1.14*CM1A charge model, leading to a mean unsigned error (MUE) of 1.5 kcal/mol with respect to experimental HFE data. The performance of CM1A charges was improved by adding Localized Bond Charge Corrections (LBCC), by which small charge adjustments are made to the partial charges for atoms in problematic bond types such as, CT-OH in aliphatic alcohols. Only 19 LBCCs were enough to reduce the errors with the 1.14*CM1A charges for the 426 HFE values to only 0.61 kcal/mol. These adjustments give rise to the 1.14*CM1A-LBCC charge method which can also be provided by the LigParGen server.
In general, quantum mechanics population analysis methods distribute the total electron density of a molecule into partial charges centered on each atom of the molecule. As partial charges are not observables, there are different ways to partition the electron density. The CM1A method uses the Mulliken population analysis from the electron density obtained by the AM1 method from the ligand geometry. Mulliken charges for an atom A are computed using the following equation: where is the partial Mulliken charge, is the nuclear charge of the atom A and is the electron density assigned to atom A as described by the equation:
where N is the total number of electrons in the molecule, is the molecular orbital coefficient for the atomic orbital and is the QM overlap integral. This electron density definition is based on the linear combination of atomic orbital–molecular orbital (LCAO–MO) method where the molecular electronic distribution per each molecular orbital is defined each as a linear combination of atomic orbitals (n).
The CM1A charges are then computed using a multilinear transformation of the Mulliken charges based in the computed bond orders to improve the molecular dipole moment using empirical parameters. Then, for neutral molecules, the 1.14*CM1A model scales the charges by a factor 1.14, which was fitted to improve the agreement of the HFEs to the experimental values (16 (link)). If the total charge of the molecule is not zero, partial charges are not scaled. It should be noted that, as in all quantum mechanics based charges, the CM1A charges can have some variations due to the molecular geometry. The typical variations observed in our tests are in the 0.03–0.05 e range, with a few cases involving intramolecular hydrogen bonds reaching 0.1e.
A later evaluation of HFEs for a set of 426 organic molecules showed that some moieties such as phenyl rings, aldehydes or ketones are not well parameterized by the 1.14*CM1A charge model, leading to a mean unsigned error (MUE) of 1.5 kcal/mol with respect to experimental HFE data. The performance of CM1A charges was improved by adding Localized Bond Charge Corrections (LBCC), by which small charge adjustments are made to the partial charges for atoms in problematic bond types such as, CT-OH in aliphatic alcohols. Only 19 LBCCs were enough to reduce the errors with the 1.14*CM1A charges for the 426 HFE values to only 0.61 kcal/mol. These adjustments give rise to the 1.14*CM1A-LBCC charge method which can also be provided by the LigParGen server.
