Overview

Freeform, calculates some thermodynamic properties, useful for drug discovery, for small molecules.

Caution

freeform -calc conf takes over 6 Gigabytes of memory by default.

The conformer generation step of freeform -calc conf uses a default maximum conformer limit of 40000 conformers, leading to a high memory usage of over 6 Gb of memory. Reducing the maximum conformer limit with the -maxconfs flag will significantly reduce memory usage, although this may reduce the accuracy of the conformer free energies, especially with molecules containing many rotatable bonds. If memory usage is an issue, we recommend running a calculation using maxconfs 20000, and if this maximum is not reached in the initial conformer generation step (check the line containing “generating conformers… ” in the log file) then there will be no loss in accuracy compared to the default 40000.

Note

The graph in the pdf output of freeform -calc conf may not show all minima

The “dG vs Erel” graph in the pdf output of freeform -calc conf uses default axes spanning only 0 to 7 kcal/mol for conformer dG and 0 to 5 kcal/mol for Erel; generally the whole unbound ensemble contains minima above these ranges (sometimes the majority of minima). The data for all the minima are contained in both the output log and csv files; the graph is intended only to show minima that could potentially contribute significantly to the room-temperature ensemble, hence the limited range of the axes. The axes are extended somewhat to show tracked minima, but beyond 30 kcal/mol in either dG or Erel not even these data are shown in the graph.

Note

It is possible to get a negative Local Strain Energy with -solvent PB

Ordinarily, Local Strain Energy can never be negative because the energy can only decrease once the restraints are removed and the ligand is allowed to freely minimize. With -solvent PB, PB single-point solvation energies are taken of the restrained minimum and the corresponding freely minimized minimum. There are two reasons why this could result in a negative Local Strain Energy. The first is due to the precision of the PB calculation being around 0.2 kcal/mol: if the true restrained and free minima are within 0.2 kcal/mol the restrained minimum could end up with a slightly higher PB solvation energy simply due to the imprecision. The second reason is that the Sheffield solvation energy used in minimizing from the restrained to the free minimum may simply differ in the opposite direction from the PB solvation energy for the same minima.

Note

AM1BCC ELF10 charging may use fewer than 10 conformers for charging

AM1BCC ELF10 charging is designed to average the AM1BCC charges from 10 conformers chosen from the 2% of the conformer population having the Electrostatically Least-interacting Functional (ELF) groups. 10 conformers from 2% means there must be at least 500 conformers to start with; ligands which have fewer rotatable bonds may not have this many. In such cases, the AM1BCC ELF10 method is designed to take all the conformers in the 2% ELF population. For example if the starting conformer set has 327 conformers, all 6 conformers in the 2% ELF population will be used. With 50 or fewer conformers, a single ELF conformer with be used. When more than one conformer is used, the log file line starting with “Semiempirical charge averaging” tells how many were used.