Editing ChargeCalculator:FAQ (section)

=How do I choose a suitable EEM parameter set?=

EEM, the empirical method used by '''ACC''' to calculate atomic charges, relies on empirical parameters. Many EEM parameter sets have been published in literature. They are available in '''ACC''' as ''built-in sets'', each having a unique identifier. By default, '''ACC''' tries to suggest some suitable set of EEM parameters based on the type and atomic composition of the molecule you loaded. If '''ACC''' is unable to perform this default selection, or you feel the default choice is not optimal, you will need to make sense of the various sets available.

You will notice that the table with parameter sets is organized first according to the ''target''. This is because the applicability domain of a given EEM parameter set is generally limited to the target molecules. Therefore, in general, one should prefer an EEM parameter set which is meant for the type of molecules of interest. This is not an absolute rule. In fact, we have observed that some EEM parameter sets developed for biomolecules perform very well for organic molecules as well. However, the opposite is not true. Therefore, it's better to choose an EEM parameter set according to the type of input molecule.

{| class="wikitable"
 |-
 |'''Target'''
 |-
 |''Description:'' type of molecules that are likely to be well described using a specific set of EEM parameters
 |-
 |''Possible values:'' organic molecules, drug-like molecules, proteins, etc.
 |}

Another requirement is that the set cover all atom types in the input file. This means that all chemical elements present in the input molecule should be on the list of ''Atoms'', and nothing should be listed at ''Missing atoms''. If all built-in sets report ''Missing atoms'', you will probably have to ''Add'' a new EEM parameter set where all necessary EEM parameters are provided (see below how).

{| class="wikitable"
 |-
 |'''Atoms'''
 |-
 |''Description:'' List of atom types covered by the EEM parameter set. Depends on the type of molecules used to produce reference data during the development of the EEM parameters.
 |-
 |''Possible values:'' H, C, N, O, Cl, etc.
 |}

{| class="wikitable"
 |-
 |'''Missing Atoms'''
 |-
 |''Description:'' List of atom types present in the input file but not covered by the EEM parameter set. These atoms will not be included in the atomic charge calculation using this EEM parameter set.
 |}

Further, one should consider the ''approach'' used during the development of the parameters. EEM parameters are generally developed based on reference quantum mechanical (QM) calculations. A QM calculation is characterized by the setup of the wave function calculation (theory level, basis set, environment), and the type of observables that will be calculated and interpreted. Most commonly, QM reference data used for the development of EEM parameters consists of atomic charges, which are derived from the observable electron density according to a specific ''charge definition'', meaning a procedure used to partition the molecular electron density, or to deduce the electrostatic contribution of each atom. Because atomic charges are not physical observables and have only a conceptual character, there is no unique ''charge definition'' that is universally accepted. Rather, a score of ''charge definitions'' have been published and are in use, each with their own strengths and weaknesses. 

We denote as ''approach'' any association of a QM calculation setup and ''charge definition''.

{| class="wikitable"
 |-
 |'''Approach: QM Method, Basis Set, Population Analysis'''
 |-
 |''Description:'' association of a QM calculation setup and ''charge definition''. Gives the nature of the reference QM data used during the development of the EEM parameters. The applicability domain of an EEM parameter set is closely related to the applicability domain of the reference QM data. 
 |-
 |''Possible values:'' 
*''QM Method'' - level of theory used to solve Schr&ouml;dinger's equation - HF, B3LYP, etc.
*''Basis Set'' - set of basis functions used to solve Schr&ouml;dinger's equation - 6-31G*, STO-3G, etc.
*''Population Analysis'' - charge definition used after solving Schr&ouml;dinger's equation to partition the molecular electron density, or to deduce the electrostatic contribution of each atom - MPA (Mulliken population analysis), NPA (Natural population analysis), MK (Merz-Kollman scheme for fitting to electrostatic potentials), etc.
 |}

The applicability domain and maximum expected accuracy of an EEM parameter set is closely related to the corresponding QM charges obtained by that particular ''approach''. The maximum accuracy for a particular application of any set of EEM parameters is given by the ''charge definition'' used during its development. Therefore, if available, pick an EEM parameter set with a higher level of theory, and most importantly a ''charge definition'' suitable for the subsequent application of the atomic charges (what you have in mind to do with the charges). For example, pick MK charges if you plan to run simulations, NPA charges if you plan to interpret reactivity, MPA charges if you plan to do QSPR, etc.

The performance of a given EEM parameter set is further influenced by the procedure used when fitting the EEM parameters to the reference data (size and nature of the QM reference dataset, fitting and optimization algorithms, etc.). Sets with higher ''training set size'' should theoretically be more robust. The ''data source'' should refer to molecules of the same type as your molecule of interest.

{| class="wikitable"
 |-
 |'''Training Set Size, Data Source'''
 |-
 |''Description:'' Number and type of molecules used to produce reference data during the development of the EEM parameters.
 |}

Finally, to help you make decisions faster, we have included a very basic grading system in the form of the ''priority'' descriptor given for each EEM parameter set. When in doubt, pick a parameter set with a low value of the ''priority'' descriptor (1,2..).

{| class="wikitable"
 |-
 |'''Priority'''
 |-
 |''Description:'' Very basic grading system. Serves mainly to identify a suitable default setup. Currently curated manually. 
 |-
 |''Possible values:'' For EEM parameter sets focused on ''biomolecules'', priorities are assigned based on their performance in the external validation stage of their development. For sets focused on organic molecules, priorities are assigned based on year of publication, level of theory of the QM reference data, and the results of a small in-house QM benchmark on paracetamol. Lower values are preferred.
 |}

All in all, it is always good to try several parameter sets, and draw conclusions based on the trends observed in most sets of results. The EEM implementations in '''ACC''' are all computationally efficient, so running calculations with multiple parameter sets is not a problem.