Ring Conformations: ring_conf
It can be difficult, or at least computationally demanding, to find low-energy conformations for the flexible ring systems within a structure. The ring_conf tool attempts to do so by identifying ring systems in the structure, then seeking suitable ring templates from its collection, and using these templates to generate good ring conformations.
Briefly, ring_conf examines the molecule to identify groupings of flexible rings, referred to as ring systems, that require a template. Many aromatic ring systems are recognized as such and no template will be sought for them and the input geometry will be used. However, aromatic rings within ring systems containing flexible rings need special attention. If they share 2 or more atoms with a flexible ring then they influence the conformation of the flexible ring and thus must be considered part of the ring system for template matching. However, if they do not share 2 or more atoms with a flexible ring they are not included in ring system that must be matched by a template. In this way, ring systems in which flexible rings are connected by non-flexible rings that do not overlap with flexible rings may be split into separate ring systems for templating purposes. Once the process of identifying portions of the molecule that require ring system templates are found, templates are sought separately for each such portion. Ring systems for which templates cannot be found retain the input geometry for the ring system. Template matching has some flexibility in that enantiomers may be matched and protonation states of sp2 or sp3 nitrogen atoms need not match. Also, amide bonds in rings are matched by C=C if a specific template is not found. The template library has more than 770 templates, many of which have multiple conformations. Templates in the library include inversions of non-quaternary sp3 nitrogen atoms in their collections of conformations.
After the template identification for the ring systems is complete, the conformational energies that depend on the ring conformation are estimated in a crude manner. The energy of each ring system is estimated separately based upon the ring conformation energies recorded in the template database, the axial-equatorial energies of the attachments and a pair-wise short range repulsion between base atoms for each attachment (the atoms directly bonded to atoms in the rings). The total ring system energy for a particular selection of conformations for all ring systems in a structure is obtained by adding together the energies for these conformations in each ring system.
By default, only the structure with the lowest estimated energy for each input structure is written to the output structure file. However, multiple structures with different ring conformations can be saved (options -e, -n, and -N) using different selection criteria (option -c).
While ring_conf is focused on providing conformations for the flexible ring systems in the structure provided, it can also attempt to adjust the conformations of portions of the structures outside such systems, depending on the linear generation method (see the -l option below). We generally recommend using -l 3, which instructs ring_conf to adjust the linear portions of the molecules so that they adopt extended conformations.
Syntax:
ring_conf [options] input-file.mae output-file.mae
You must have a LigPrep license to run ring_conf. For information on the options, see ring_conf Command Help.
Additional output files:
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jobname |
Structures for which either templates were missing or the relative energies of axial vs. equatorial geometries for attachments were missing. |
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jobname |
Structures for which |
Limitations:
Missing Templates: The collection of templates for flexible ring systems is incomplete. In our trials, typically ring_conf did not find templates for all ring systems present for a small percentage of the valid input structures. However, we expect that the rate of misses will vary dramatically. Flexible ring systems for which templates are not found are simply treated by ring_conf as though they were rigid. At present, ring_conf does not support the ability to directly add templates to the template library; however, you can specify a custom location for additional templates, as described below.
Structures for which templates were not found are written to a Maestro file named jobname_rcout_tmpl_att_prob.maegz. This file is copied back to the working directory, or is included in the archive that is copied back to the working directory when running LigPrep. You can use this file to generate templates with the ring_templating utility—see ring_templating: Creating Ring Conformation Templates for more information. When these templates are placed in your Schrödinger user resource directory, the distribution, or the location specified by the environment variable SCHRODINGER_RING_TEMPLATE_DIR, they are used by ring_conf.
The Maestro property i_lp_ring_sampling_problem is added to the structures, to indicate the cause of failure. A value of 1 means that templates were not found for any of the ring systems. A value of 2 indicates that templates were found for some ring systems but not others, while 3 indicates an unclassified problem.
Attachment Geometries for Missing Templates: Under some circumstances, attachments to flexible ring systems for which templates were not found are placed on top of each other if a value of 2 or 3 is given for the -l option. However, these geometries usually do not cause problems in subsequent processing by premin and bmin within LigPrep protocol.
Misidentification of Smallest Set of Smallest Rings: In very rare instances, the software that identifies the rings within ring systems, particularly fused ring systems, omits some rings. In such cases, it may not be possible to find a suitable template even if one is present.
Overlapping Atoms: ring_conf generates low-energy ring conformations using criteria that depend on features that are local to individual ring systems. The relative positions of portions of a molecule that are not directly associated with a single ring system are not taken into account, and in some instances may lie too close to each other. Within the LigPrep context the follow-up minimization and optional conformational search using MacroModel are expected to eliminate nearly all such problems.