ConfGen Opcodes
ConfGen is a very flexible and fast conformational searching technology for ligands, supported by the opcodes listed in this topic. A ConfGen license is required to use the ConfGen opcodes. The opcodes are linked below:
CGO2 — additional ConfGen Options
CGO3 — Additional ConfGen Options for enhanced sampling of weak torsional potentials
CGO5 — Additional ConfGen Options for functional groups that are close to polar hydrogens
CHYD — Suppress Hydrogen Bond Electrostatics
CGEN — ConfGen
|
arg1 |
Maximum number of structures to request from ConfGen |
|
arg2 |
Maximum number of structures to retain while running |
|
0 |
The maximum number of conformations to retain while running is the value specified in arg1 or 10,000, whichever is greater |
|
> 0 |
This is the maximum number of conformations to retain while running |
|
arg4 |
Peripheral sampling option |
|
1 |
Rapid Sampling: only generate conformers in which at most one peripheral group is rotated away from its lowest internal energy conformation |
|
2 |
Thorough Sampling: sample all combinations of rotations of peripheral groups |
|
arg6 |
Allowable interatomic approach distance |
|
Fraction of sum of van der Waals radii which is used as a closest atomic approach limit (default: 0.25) |
|
|
arg7 |
Enhance planarity of groups with bonds between sp2 atoms |
|
Increase the torsional potential around bonds between sp2 atoms, such as aromatic rings, amides, and esters, whose geometry should ideally be planar. |
|
|
0 |
Default. Do not enhance planarity of groups with bonds between sp2 atoms. |
|
1 |
Enhance planarity of groups with bonds between sp2 atoms. |
|
arg8 |
Verbose reporting on |
Related DEBG flag: 200.
CGOP — ConfGen OPtions
CGOP is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options for the ConfGen facility.
|
arg1 |
Sampling symmetric terminal groups |
|
Terminal |
|
|
0 |
do not sample these symmetric terminal groups |
|
1 |
sample such terminal groups |
|
arg2 |
Ring conformation sampling |
|
Ring sampling is done by matching the rings in the molecules with templates for which the low-energy conformers have been previously identified. Two such template matching systems are supported:
|
|
|
The specific templating system has broader coverage (several hundred templates) and the template conformations were generated using MacroModel searches employing the MMFFs force field. |
|
|
0 or 2 |
use the specific templating system ( |
|
1 |
use the general templating system |
|
3 |
do not sample ring conformations |
|
arg3 |
Minimization of generated structures |
|
0 |
minimize generated conformations using at most the number of iterations in the |
|
−1 |
do not minimize the generated conformations, but estimate the current energy, superimpose the generated conformations, and eliminate redundant conformations |
|
−2 |
do not post process the conformations provided by ConfGen |
|
−3 |
do not estimate the energies for the conformations produced but superimpose the generated conformations, and eliminate redundant conformations |
|
> 0 |
minimize generated conformations using at most this number of iterations |
|
arg4 |
Non-ring amide bond conformation sampling |
|
0 or 1 |
default: vary the geometry of amide bonds |
|
2 |
retain the original amide bond geometry |
|
3 |
make amide bond geometry trans |
|
arg5 |
Maximum relative ring conformation energy in kJ/mol |
|
0 |
use default value of 48 kJ/mol |
|
> 0 |
use this value (kJ/mol) |
|
arg6 |
Upper limit on the number of combinations of ring conformations sampled |
|
0 |
use default value of 16 |
|
> 0 |
use this value |
|
arg7 |
Upper limit on the number of ring conformations sampled per ring system |
|
0 |
use default value of 8 |
|
>0 |
use this value |
|
arg8 |
Maximum relative ConfGen internal energy |
|
0 |
use default value of 50.0 kJ/mol |
|
> 0 |
use this value (kJ/mol) |
, 
and 
groups are never sampled by ConfGen. Sampling the conformations of other types of symmetric terminal groups is sometimes not useful. The identification of such groups is complex but boils down to an atom with identical groups attached to it. These groups can be monoatomic or composed of atoms with only 2 or 3 hydrogen atoms bonded to them. Checks for rotational symmetry are also imposed (e.g. if there are two groups but they do not lie 180° apart from each other, they would need to be sampled). Typical examples include 
, 
, and 
.CGO2 — additional ConfGen Options
CGO2 is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options for the ConfGen facility.
|
arg1 |
Carboxylic acid bond conformation sampling |
|
0, 1 |
default: vary the geometry of carboxylic acid bonds |
|
2 |
retain the original carboxylic acid bond geometry |
|
3 |
make carboxylic acid bond geometry trans |
|
arg3 |
Method for estimating the number of degrees of freedom |
|
When AUOP arg5 is greater than zero, the number of conformations to sample is given by the product of this value and the number of degrees of freedom. This argument controls which method is used to estimate the number of degrees of freedom. |
|
|
0, 2 |
Use ConfGen’s internal estimate for the number of degrees of freedom, which is given by the number of rotatable bonds + log2(number of ring conformation-nitrogen atom inversion combinations) |
|
1 |
Use the number of rotatable bonds given by MacroModel. |
|
arg4 |
Include the most extended conformers |
|
When selecting a subset of conformers from those produced by ConfGen include the arg4 most extended conformers first. In each conformer the largest distance between any two heavy atoms is calculated. The ratio of this value to the largest such distance amongst all of the conformations for this molecule is used as a measure for how extended the conformer is. |
|
|
arg5 |
Van derWaals radius scaling factor for close atomic approaches |
|
ConfGen rejects conformations with atoms closer than this factor times the sum of their van der Waals radii. |
|
|
≤ 0 |
use default value of 0.6 |
|
> 0 |
use this value |
|
arg6 |
Scaling factor for close atom gradients |
|
ConfGen internally minimizes structures on a simple potential function that includes a penalty term for close approaches of atoms. This argument specifies the scaling factor for this penalty term. |
|
|
≤ 0 |
use default value of 1.0 |
|
> 0 |
use this value |
|
arg7 |
Minimum van derWaals atom radius used for rejecting structures |
|
If the van der Waals radius for an atom is less than this value, use this value instead to determine when atoms are too close within a candidate structure. |
|
|
0 |
use default value of 1.0 Å |
|
> 0 |
use this value |
CGO3 — Additional ConfGen Options for enhanced sampling of weak torsional potentials
CGO3 allows the user to activate and adjust enhanced ConfGen capabilities for sampling weak torsional potentials. CGO3 is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options for the ConfGen facility.
sp2–sp3 bonds often have only two potential minima and usually have low barriers to rotation. As a result, environmental factors can force such bonds to adopt conformations that do not closely resemble either minimum. This is a concern when trying to reproduce the bioactive conformations of ligands. CGO3 activates functionality that detects rotatable bonds with low barriers to rotation and replaces the original torsional potential with a simple cosine function with a user-specified periodicity. The cosine function is shifted so that one of its minima coincides with the deepest minimum in the original torsional potential. ConfGen then systematically samples all combinations of minima in all torsional potentials including the new artificial minima for the cosine functions.
If CGO3 is not present then the original weak potential and its minima are used. The presence of CGO3 activates replacement of weak potentials by cosine functions.
|
arg1 |
Cosine function frequency |
|
Number of times the cosine function repeats when rotating by 360 degrees. This also is the number of minima spaced 360/arg1 degrees apart that will be sampled. |
|
|
0 |
use the default frequency: 6 (spacing of 60°). |
|
> 0 |
use this frequency (maximum 36). |
|
arg5 |
Energy range |
|
The difference in energy between the minima and the maxima in the cosine potential. This energy range is used to determine which torsional potentials are weak. If the extremes of the original torsional potential all lie within arg5 of each other then the original potential is deemed weak and is replaced by a cosine function. |
|
|
0 |
use the default energy range 12 kJ/mol |
|
> 0 |
use this value (kJ/mol) |
|
arg6 |
Maximal original energy for new minima |
|
All arg1 minima of the cosine potential are normally sampled by ConfGen. Some of these minima may correspond to relatively high potential regions of the original potential. The value in arg6 sets an upper bound on the energy difference between the lowest energy in the original potential and the energy in the original potential corresponding to a minimum in the cosine potential. If that bound is exceeded then this minimum in the cosine function is not sampled. |
|
|
0 |
do not eliminate minima |
|
> 0 |
use this value as the upper bound on the energy difference (kJ/mol) |
|
arg7 |
restraining potential prefactor |
|
If the conformations are being minimized inside MacroModel itself, the dihedrals with weak torsional potentials have a periodic flat-bottomed cosine restraining potential applied. This value is the prefactor for the cosine potential. |
|
|
0 |
use 1000 kJ/mol |
|
> 0 |
use this value (kJ/mol) |
|
arg8 |
Half-width of the flat-bottom potential |
|
If the conformations are being minimized inside MacroModel itself, the dihedrals with weak torsional potentials have a periodic flat-bottomed cosine restraining potential applied. This value is the half width of the flat portion of the potential. |
|
|
0 |
use 10 degrees |
|
> 0 |
use this value (degrees) |
CGO4 — Additional ConfGen Options for rejecting conformations with close contacts between charged functional groups
CGO4 allows the user to activate and adjust enhanced ConfGen capabilities for rejecting conformations that have formally charged functional groups that lie too close to each other. CGO4 is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options related to this facility.
ConfGen inherently generates conformations without considering electrostatics. This can occasionally lead to conformations that have functional groups with a formal charge of the same sign lying near each other. If minimization or energy filtering of conformations is not done inside MacroModel itself (CGEN arg3 = −1 or −2, respectively) these conformations may end up being saved in the output structure file. CGO4 turns on a penalty mechanism that can exclude such conformations within ConfGen itself. The penalty for conformation k is calculated from the fractional formal charges qi on the atoms using the expression
where the sum runs overall all pairs of atoms i and j that are separated by at least 3 bonds, and
where A and s are constants and rij is the distance between atoms i and j.
If 
where Pmin is the smallest penalty for any of the conformations then the conformation is eliminated within ConfGen.
|
arg5 |
Standard deviation of the Gaussian penalty, s |
|
0 |
use 5 Ang |
|
> 0 |
use this value (Ang) |
|
arg6 |
Maximum value for the Gaussian, A |
|
0 |
use 2.5 |
|
> 0 |
use this value |
|
arg7 |
Relative penalty cutoff, Pcutoff |
|
0 |
use 0.75 |
|
> 0 |
use this value |
CGO5 — Additional ConfGen Options for functional groups that are close to polar hydrogens
CGO5 allows the user to activate and adjust enhanced ConfGen capabilities for rejecting conformations that have polar hydrogen atoms too close to groups with positive formal charges, and also to reward intramolecular hydrogen bonds. CGO5 is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options for the ConfGen facility.
ConfGen inherently generates conformations without considering electrostatics. This can occasionally lead to conformations that have functional groups with a bond to a hydrogen close to and pointing towards a functional group with a positive formal charge. These conformations may end up being saved in the output structure file particularly if minimization or energy filtering of conformations is not done inside MacroModel itself (CGEN arg3 = −1 or −2, respectively). CGO5 turns on a penalty mechanism that can exclude such conformations within ConfGen itself. The penalty for conformation k is calculated from the fractional formal charges qi on the atoms using the expression
where the sum runs over all all pairs of polar bonds to hydrogens i and positively charged atoms j. Polar bonds to hydrogens involve a hydrogen atom (H) bonded to a O or N atom. The O or N atom must be at least three bonds away from atom j. The penalty term is defined by
where pHj and pONj have the same functional form,
A and s are constants and rXj is the distance between atoms X and j.
If 
where Pmin is the smallest penalty for any of the conformations then the conformation is eliminated within ConfGen.
Another situation that can be encountered is when a polar hydrogen from a cation is too close to an aromatic or pi ring system. In this case, such conformations are rejected if the polar hydrogen is closer to the ring than a specified cutoff.
Similarly, ConfGen might not find conformations in which there is a hydrogen bond: a polar bond to hydrogen pointing towards a hydrogen-bond acceptor (an atom with a partial negative charge). For such situations, a reward is applied that has the same form as the penalties, and the sum is over negatively-charged atoms j. No cutoffs are applied to the reward term.
|
arg2 |
Add rewards for intra molecular hydrogen bonds |
|
0 |
do not reward intramolecular hydrogen bonds. |
|
1 |
reward intramolecular hydrogen bonds. arg5 and arg6 are used to specify the reward. |
|
arg5 |
Standard deviation of the Gaussian, s |
|
This value is used as specified for penalties, and multiplied by 0.2 for rewards. |
|
|
0 |
use 5.0 Å |
|
> 0 |
use this value (Å) |
|
arg6 |
Maximum value for the Gaussian, A |
|
This value is used as specified for penalties, and multiplied by 10.0 for rewards. |
|
|
0 |
use 1 |
|
> 0 |
use this value |
|
arg7 |
Relative penalty cutoff, Pcutoff |
|
0 |
use 0.25 |
|
> 0 |
use this value |
|
arg8 |
Distance cutoff between cation-H and pi ring system, in angstroms |
|
0 |
use 1.0 |
|
> 0 |
use this value |
CGO6 — Additional ConfGen Options for rejecting conformations with close contacts between nonhydrogen atoms
CGO6 allows the user to activate and adjust enhanced ConfGen capabilities for rejecting conformations that have too many nonhydrogen atoms in close proximity. CGO6 is one of a number of opcodes (CGOP, CGO2, CGO3, CGO4, CGO5, CGO6) that provide access to additional options for the ConfGen facility.
Bioactive conformations tend to be relatively extended. ConfGen can generate conformations in which topologically distant parts of the ligand lie close to each other. These conformations may end up being saved in the output structure file. CGO6 turns on a penalty mechanism that can exclude such conformations within ConfGen itself particularly if the groups approaching each other are rings. The penalty for conformation k is calculated using the expression:
where the sum runs over all all pairs of nonhydrogen atoms i and j that are at least three bonds away from each other. The penalty term is defined by
A and s are constants and rXj is the distance between atoms X and j.
If 
where Pmin is the smallest penalty for any of the conformations then the conformation is eliminated within ConfGen.
|
arg5 |
Standard deviation of the Gaussian penalty, s |
|
0 |
use 2.5 Å |
|
> 0 |
use this value (Å) |
|
arg6 |
Maximum value for the Gaussian, A |
|
0 |
use 1 |
|
> 0 |
use this value |
|
arg7 |
Relative penalty cutoff, Pcutoff |
|
0 |
use 1.00 |
|
> 0 |
use this value |
CHYD — Suppress Hydrogen Bond Electrostatics
The presence of this opcode suppresses electrostatic interactions between the charges arising from the bond dipole between the H and donor atom (O, N or S atom) and acceptor atom (N, O, S or F) within a ligand. The exception is that sp2 nitrogen atoms with 2 or 3 non-hydrogen attachments or nitrogen atoms that carry a positive formal charge cannot be considered acceptors.
Intramolecular hydrogen bonds in ligand-sized molecules can have a strong effect on the relative energies of conformations and yield compact conformations as the global minimum energy state. This effect is partially mitigated by using solvation treatments such as a distant dependent dielectric or GB/SA. However, intramolecular hydrogen bonds still can have an significant influence. In a protein environment, intraligand hydrogen-bonding competes with ligand-protein hydrogen bonding. In addition, ligand conformations in ligand protein complexes are usually extended rather than compact. Thus when modeling just the ligand it can be advantageous to suppress intra-ligand hydrogen bonding interactions to better imitate ligand conformations within ligand-protein complexes. Since the electrostatic contributions dominate hydrogen bond energetics and eliminating excluded volume effects can lead to problematic behavior, the CHYD opcode simply turns off the electrostatic portion of the hydrogen bonding interaction. CHYD does not affect the electrostatics of donor and acceptor atoms if they interact via a dihedral angle potential.
|
arg1 |
Control hydrogen-bond electrostatics |
|
−1 |
Use normal hydrogen-bond electrostatics. |
|
0,1 |
Suppress hydrogen-bond electrostatics. |