Flare Align

Options

Basic

Column containing reference molecule structures

The column in the first input datatable containing the reference molecules.
The reference molecule is a molecule that is used in alignment experiments to fit other molecules. You can have multiple (up to 9) reference molecules however if there is more than one reference, then the references must be correctly aligned to each other, and the other molecules will be aligned to all of the references simultaneously.

Column containing the molecules to be aligned

The column in the second input datatable containing the molecules to be aligned (the moving molecules) to the reference molecules.

Column containing (optional) protein structure

The column in the third input datatable containing an optional protein structure or an alternative source of excluded volume to guide the alignments.

Speed

Speed of operation of Flare Align. Choose from (in order of decreasing speed, but increasing thoroughness): Quick, Normal or Exhaustive. Note that changing this option will alter the values of several other options.

Align using maximum common substructure

Uses a special conformation hunt where the common substructure with the reference molecule is held in the same conformation as the reference molecule, and groups that are not part of the common substructure are conformation hunted. The different MCS matching rules available allow you to specify how the common substructure routine handles hybridization and element differences.

Only score molecules

Does not generate conformations or allow molecules to move, just score molecules in their input positions. The input molecules must be 3D.

Conformer Hunt

Skip conformation hunt

If checked each record is assumed to be a separate molecule in a fixed conformation. The molecule will be aligned but conformations will not be generated.

Generate at most this number of conformations

The maximum number of conformations to generate for each molecule. Larger values take longer but give better alignments. Values of 50-200 are recommended and a maximum of 2000 can be set.

No. of high-T dynamics runs for flexible rings

Most small rings are handled using a ring conformation library. Conformations for rings that are not found in the library are sampled using high-temperature (~600K) dynamics with energy initially distributed into torsional degrees of freedom. The number of dynamics runs (and hence the degree of ring conformation sampling) is set by this value. Values of 2-10 are recommended. Values above 5 make little difference to flexible rings of fewer than 8 atoms.

Gradient cut-off for conformer minimization

All conformers found are minimized using the XED force field. This option sets the gradient cut-off at which the minimization is terminated. Values that are too small lead to insufficient sampling of conformational space and long run times. Values that are too large can lead to unrealistic structures being generated. Values of 0.1 kcal/mol/A to 1.0 kcal/mol/A are recommended with values at the smaller end of the range being preferred if the 'Include coulombics' option is not checked.

Energy window

Conformations that have a minimized energy that is outside the energy window are discarded. The window is calculated from the lowest energy conformation that has been found. The ideal value for this option depends on the 'Gradient cut-off for conformer minimization' and 'Include coulombics' options. The best results when the 'Include coulombics' option is not checked are obtained by minimizing to a low gradient (0.1 or better) and applying a smaller energy window (3 kcal/mol) but this significantly increases the time for the calculation. Checking the 'Include coulombics' option requires a significantly larger energy window for large molecules (12 kcal/mol) as these can form very low energy collapsed and internally H-bonded structures.

RMS filter for conformation generation

Sets the similarity threshold below which two conformers are deemed identical. This effectively controls the coarseness of the sampling of conformational space. A low value leads to conformations that are only marginally different, while using a large value means that a conformation near the 'correct' one may not be generated. Values of 0.5 A to 1.0 A are recommended: values at the higher end of the range are more appropriate for larger, more flexible molecules.

Acyclic secondary amides handling

Specify how the conformation hunter is to handle amides. Note that this option has no effect on ureas, urethanes, and thioamides as the N-C bonds in these are always treated as rotatable.

• Force amides trans - forces all secondary amides to adopt the trans geometry.
• Use input amide geometry - leaves secondary amides in the geometry that they were in the input file and sets them as non-rotatable. As a result, if the input molecule was drawn with a cis amide then only conformations with cis amides will be generated.
• Allow amides to spin - allows the amide bond to spin, so a mixture of cis and trans amides can be generated.

Include coulombics

If checked, then the conformer generation process uses the full force field, including long-range electrostatics. Better conformer populations are usually generated with this option turned off (unchecked).

Remove Boats

Filter out any conformations that contain 6-membered rings in a boat or twist-boat conformation. By default, they will be filtered out only if sufficiently high in energy that they are removed by the Energy Window setting.

Alignment

Number of alignments to generate

The number of alignments to generate for each molecule. The default is 1.

Score method for multiple references

If there is more than one reference, the default behaviour ("Weighted Average") is to calculate the score of each alignment as the average of the scores to each reference. Set this option to "Maximum" if you want the score for each alignment to be the single highest score to any of the reference molecules. If there is only one reference molecule scoring by "Weighted Average" or "Maximum" give the same results.

Shape weight

The relative weight assigned to shape (as opposed to field) similarity. Values must be between 0.0 (all field) and 1.0 (all shape). On most datasets the default of 0.5 shape similarity gives good results.

Conformers of achiral molecules can be inverted

Allows conformers of achiral molecules to be inverted if that gives a better alignment. Chiral molecules are never inverted. This must be checked if the imported conformations were exported from Flare, as the conformer population filters out mirror image conformations.

Field constraints

Consists of a set of numbers in the form index,size,reference e.g. 16,2.5,1 means that the field point with index 16 on the first reference should have a constraint of 2.5 applied to it. The index argument is the index of the field point in the list of field points (i.e. the first field point is index 1). You may have more than one field constraint specified, separated by newlines. The reference index is optional and will default to the first reference molecule provided. Please refer to the Flare manual for a detailed explanation of field constraints. For this option to work correctly, the input reference molecule must contain a "_cresset_fieldpoint" tag with the field point data in it.

Pharmacophore constraints

Consists of a set of numbers in the form index,type,strength,reference e.g. 16,d,3.2,1 means that the pharmacophore constraint on the atom with index 16 should be a donor with strength of 3.2 applied to it. You may have more than one field pharmacophore specified, separated by newlines. The characters for each type are 'd'=Donor, 'a'=Acceptor, '+'=Cation, '-'=Anion, 'm'=Metal binder and 'v'=Covalent. The reference index is optional and will default to the first reference molecule provided. Please refer to the Flare manual for a detailed explanation of pharmacophore constraints.

Protein hardness

• Soft - A small penalty is applied for each atom of the ligand that overlaps with a protein atom and each protein atom is treated as relatively "squashy". This option works well where you are prepared to accept results that may have some overlap, but you want to remove gross clashes with the protein.
• Medium - A medium penalty is applied.
• Hard - A large penalty is applied, and each protein atom is treated as relatively firm. Use this option where you want to remove all results that impinge on the protein structure.

Only has an effect if a protein is specified.

Scoring metric

• Dice: default similarity metric in the current and previous versions of Flare.
• Tanimoto: monotonic with Dice, so will not change the rank ordering of results, although the similarity values will change.
• Tversky: use this metric to set up a more 'substructure-like' or 'superstructure-like' alignment. For a substructure-like alignment (i.e aligning molecules which are substructures of the query), use Tversky with Alpha Value=0.05. For a superstructure-like alignment (i.e. aligning molecules which are larger than but include the query), use Tversky with Alpha Value=0.95.

Alpha Value

Insert a value between 0.0 and 1.0. Only available if Tversky scoring metric is selected.

SMARTS Pattern

Request that atoms matching this pattern have a higher weight when present in the MCS.

Require full ring matches

When aligning using maximum common substructure in “match atom element + hybridization” or “match atom hybridization only” matching rules, disallow partial ring matches for the MCS and force the MCS to match rings fully.

Do not allow MCS alignment to move

If checked, and if the MCS alignment method was specified, the molecule to be aligned are held fixed with the common substructures overlaid and not allowed to move, even if moving would improve the similarity score.

Advanced

Add column containing log

If checked, the log of the conformer generation and alignment process for each molecule is added as a column 'FlareAlign_Log'.

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