Sage-2.2.0

Repository for re-fitting Sage 2.2.0. This re-fit addresses issues with the geometry of epoxide groups and sulfamide groups, as well as introduces some new 5-membered ring internal angles, removes redundant parameters, and simplifies the SMIRKs pattern of one torsion. This is a partial valence re-fit, where we re-fit bonds, angles, and proper torsions.

Contributions for this release include changes from @amcisaac and @pavankum, benchmarking results and infrastructure from @amcisaac, @ntBre, @mattwthompson, @j-wags, @megosato, @hannahbaumann, and @lilyminium, with valuable feedback from @lilyminium, @trevorgokey, @chapincavender, @davidlmobley, @leeping, @ChristopherBayly, Bill Swope, and the team @openforcefield.

Fitting pipeline

The code that was used to produce the fit is all included here, and should be reproducible. The fit is performed in several steps, with instructions for how to run each step in the README file in each directory:

1. 01_generate-forcefield: Generate an initial "template" force field, which contains the desired SMIRKs patterns for all bond/angle terms, the desired SMIRKs patterns and initial values for all torsion terms, and the desired final value for all other parameters such as electrostatics.

2. 02_curate-data: Download and filter/curate the optimized geometry and torsion drive datasets to use for the fit. Determine which parameters to optimize based on dataset coverage.

3. 03_generate-initial-ff: Generate initial values for the bond and angle terms of the force field using the Modified Seminario Method.

4. 04_fit-forcefield: Fit the force field bonds, angles, and proper torsions to the data using ForceBalance.

5. 05_benchmark_forcefield: Benchmark the force field.

Python environment

Steps 1-4 were performed with the attached conda environment, fb_196_ic_0318.yaml.

This can be installed using mamba env create -f fb_196_ic_0318.yaml

The full environment that the force field was fit using is included in the file fb_196_ic_0318_full.yaml.

Step 5, benchmarking, was performed with the yammbs-env.yaml environment found in the 05_benchmark_forcefield directory.

Changes

Changes were made to small ring internal angle parameters and to the "priors" for the force field fit, restricting how far the parameter can optimize away from its starting guess. This led to improved small ring and sulfamide geometries.

Small ring angles

The following changes were made to the small ring angles:

• a3 [*;r3:1]1~;@[*;r3:2]~;@[*;r3:3]1 moved to the end of the angle list, in order to supersede parameter a28 which was being used for epoxide internal angles prior to Sage 2.2. a28's equilibrium angle value is around 112 degrees, while the epoxide internal angle should be around 60 degrees.

• a13a [*;r6:1]~;@[*;r5;x4,*;r5;X4:2]~;@[*;r5;x2:3] was split off from a13 [*;r6:1]~;@[*;r5:2]~;@[*;r5;x2:3] to handle cases where the central atom has 4 bonds.

• a41 [*;r5:1]1@[*;r5:2]@[*;r5:3]@[*;r5]@[*;r5]1 was created as a new parameter to handle 5-membered ring internal angles.

• a41a [*;r5:1]1@[#16;r5:2]@[*;r5:3]@[*;r5]@[*;r5]1 was created as a new parameter to handle 5-membered ring internal angles where S is the central atom.

Decreased ForceBalance priors improve sulfamide geometries.

For this force field, the Force Balance priors, which control how far the parameters can optimize away from the initial value, were reduced to the following:

priors
   Angles/Angle/k :  20.0
   Angles/Angle/angle :  1.0
   Bonds/Bond/k :  20.0
   Bonds/Bond/length :  0.01
   ProperTorsions/Proper/k :  5.0
   ImproperTorsions/Improper/k :  5.0
/priors

Other changes

• Removed parameter a22a which was subsumed into a41
• t65 SMIRKs was changed from [*:1]-[#6X4:2]-[#7X3$(*~[#8X1]):3]~[#8X1:4] to [*:1]-[#6X4:2]-[#7X3:3](~[#8X1])~[#8X1:4]
• t123 was removed, as it was redundant with t123a and t124.

Benchmarking results

Overall performance

We benchmarked the Sage 2.2.0 release candidate on the industry benchmarking dataset. The results can be seen below for the ddEs, RMSD, and TFD.

Overall, Sage 2.2.0 performs very similarly to Sage 2.1.0, but a few specific geometry errors have been fixed, as described below. These improvements can be seen in the internal coordinate RMS error, shown below. Each datapoint shows the RMS error in bond length (angle, dihedral angle, and improper dihedral angle) across all bonds (angles, dihedrals, impropers) in a given molecule.

Heteroatomic 3-membered ring improvements

Treating the C-O-C epoxide internal angle with a28 in Sage 2.1.0 led to a distorted geometry that has been remedied in Sage 2.2.0. The plot below shows the internal coordinate RMS error for molecules with heteroatomic 3-membered rings, and an example geometry with the problematic bonds and angles listed.

Sulfamide improvements

The plots below show the value of the angles assigned to parameter a32 for molecules in the benchmark set that contain the sulfamide functional group, predicted with QM (y axis) and MM using Sage 2.2.0 (x-axis). The data points highlighted in purple correspond to the N-S=O angle, those in green correspond to the N-S-N angle, and the gray data corresponds to other angles covered by this parameter (e.g. C-S=O). In Sage 2.1.0, there are a number of data points that are far to the left of the diagonal, indicating that Sage 2.1.0 is vastly underestimating the angles. In Sage 2.2.0, this has been remedied.

Additionally, we show an example sulfamide molecule that highlights the improvement in these geometries with its problematic angles listed.

This improvement can also be seen in the internal coordinate RMS error for molecules that have the sulfamide moiety.

Sulfonamides remain improved

One major improvement from Sage 2.0.0 to Sage 2.1.0 was sulfonamide geometries. In Sage 2.2.0, we retain those improvements, and see further improvement in the bond and angle RMS error for molecules that contain sulfonamides. Note that sulfamides are a subset of sulfonamides, and appear in these plots as well.