Using RMSD in TorsionProfile fitting

During torsion profile fitting we allow a slight MM relaxation of the molecule with 1kcal/mol restraints on all atoms not involved in the target dihedral. We recently looked into the effect of removing the restraints and for the small set of molecules saw a very similar performance in the resulting torsion profiles. However, we see much larger RMSD deviations during the fitting as the molecule fully relaxes. In this experiment, we have changed the torsion profile target to remove the restraints and use the RMSD deviations as part of the ForceBalance objective function. This should lead to both improved PES and lower RMSD between the MM and QM predicted structures. 

 

Implementation

To do this we have looked at two possible similar methods that involve using the opt_geo target in combination with torsion profiles. This also gives us the ability to chose which internal degrees of freedom contribute to the objective function. In this example we only include dihedrals with a denom of 50, all other terms have a denom of 0.

  • Option 1, Set up a standard opt geo target for each grid point on the torsion drive with no restraints or frozen atoms. Fit these with each torsion profile.

  • Option2, Change the torsion profile target to compute the opt geo objective after each frozen optimization. This gives us a vector with the same length as the torsion profile where each value is the opt_geo dihedral only objective value, this is then added to the energy differences to give the total combined objective value.

   

return ((np.sqrt(self.wts)/self.energy_denom) * np.abs(compute.emm - self.eqm)) + ((np.sqrt(self.wts)/2 * total_ic_diff))

Option 1

This option was run by Trevor and the forcebalance tables will be updated later here we only have the validation torsion drives.

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

openff-1.0.0 RMSE 1.9340226158607 kcal/mol gaff-2.11 RMSE 1.1407243538497651 kcal/mol bespoke RMSE 0.3873825776904058 kcal/mol

 

RMSD

 

 

 

openff-1.0.0 RMSE 1.9340226158607 kcal/mol gaff-2.11 RMSE 1.1407243538497651 kcal/mol bespoke RMSE 1.0285332638632987 kcal/mol

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

 

RMSD

 

 

 

Option 2

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

initial (without restraints)

90

-45

0 - 4.027

-0.123 - 2.616

0.606

0.9598

final (without restraints)

90

90

0 - 4.027

0 - 3.907

0.277

0.2493

initial (with RMSD )

90

-45

0 - 4.027

-0.123 - 2.616

0.606

0.9598

final (with RMSD)

90

90

0 - 4.027

0 - 3.915

0.274

0.1919

initial (restraints + RMSD)

90

90

0 - 4.027

0-2.810

0.108

0.7937

final (restraints + RMSD)

90

90

0 - 4.027

0-4.036

0.092

0.2251

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

 

RMSD

 

 

 

 

Restraints + RMSD

 

 

 

 

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

initial (without restraints)

-105

135

0 - 1.355

-1.058 - 0.640

0.206

1.2118

final (without restraints)

-105

60

0 - 1.355

-0.132 - 1.192

0.170

0.1878

initial (with RMSD )

-105

135

0 - 1.355

-1.058 - 0.640

0.206

1.2118

final (with RMSD )

-105

60

0 - 1.355

-0.114 - 1.191

0.164

0.1711

initial (restraints + RMSD)

-105

120

0 - 1.355

-1.020 - 0.732

0.087

1.1512

final (restraints + RMSD)

-105

60

0 - 1.355

-0.142 - 1.229

0.084

0.190

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

 

RMSD

 

 

 

 

Restraints + RMSD

 

 

 

 

No regularization

Here we run the RMSD fit again and the no restraint standard fitting without regularization to compare the difference.

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

initial (without restraints)

90

-45

0 - 4.027

-0.123-2.616

0.606

0.9598

final (without restraints)

90

90

0 - 4.027

0-4.014

0.328

0.0117

initial (with RMSD )

90

-45

0 - 4.027

-0.123-2.616

0.606

0.9598

final (with RMSD)

90

90

0 - 4.027

0 - 4.551

0.288

0.1499

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

 

RMSD

 

 

 

 

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

State

Min(QM)

Min(MM)

Range(QM)

Range(MM)

Max-RMSD angstrom

Energy-RMSE kcal/mol

initial (without restraints)

-105

135

0 - 1.355

-1.058-0.640

0.206

1.2118

final (without restraints)

-105

-105

0 - 1.355

0-1.347

0.242

0.0237

initial (with RMSD )

-105

135

0 - 1.355

-1.058-0.640

0.206

1.2118

final (with RMSD )

-105

60

0 - 1.355

-0.112-1.124

0.159

0.1571

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

Restraints

Forcebalance result

Torsiondrive PES

Torsiondrive RMSD

RMSE

No restraints

 

 

 

 

RMSD