Energy Minimization with Open Babel: Practical Guide for Ligand Preparation

Jan 12, 2024·

Yassir Boulaamane

· 3 min read

A ligand drawn by hand, or pulled from a 2D table, is often a bad start for docking. obminimize relaxes it with a small-molecule force field. It does not produce a protein-bound pose.

Figure 1. Steepest descent is the first pass because it tolerates a bad start. Conjugate gradient is the default and is the right second pass once the worst clashes are gone. The force-field switch is separate: MMFF94, or MMFF94s, for ordinary organic ligands; UFF when the element set is the problem.

Downloaded or sketched ligands carry unrealistic bonds, angles, and overlaps. Docking those coordinates can bias the score or fail to converge. Minimization is the preprocessing step that makes the geometry a plausible gas-phase start. Commercial tools such as Chem3D do this too. Open Babel is the free command-line route.

The command

obminimize [options] input_file

-ff chooses the force field.
-sd is steepest descent.
-cg is conjugate gradient, and it is the default.
-h adds hydrogens.
-n sets the maximum number of steps. The default is 2500.
-o sets the output format, such as PDB, MOL2, or SDF.

Which force field

Force field	Typical use	Strength	Weakness
GAFF	General drug-like molecules	AMBER-compatible	Less aimed at a small ligand on its own
Ghemical	Teaching, small molecules	Light	Limited accuracy
MMFF94	Small organic ligands	Well validated	A bit heavier
MMFF94s	MMFF94 variant	Better torsions	Similar cost to MMFF94
UFF	Organics, inorganics, metals	Wide element coverage	Weaker on ordinary organics

For a drug-like ligand, use MMFF94 or MMFF94s.

SD, then CG

Steepest descent walks the gradient. It is robust and it removes high-energy clashes. It is slow once the molecule is close to a minimum.

Conjugate gradient uses the gradient and the previous search direction. It takes fewer steps near the minimum. It can fail if the start is still far away.

So the order is SD first, CG second.

Two recorded commands

MMFF94 with steepest descent, hydrogens added, PDB out:

obminimize -sd -ff MMFF94 -h ligand.mol2 -o pdb ligand_min.pdb

UFF with conjugate gradient, for a metal complex, SDF out:

obminimize -cg -ff UFF metal_complex.mol2 -o sdf metal_min.sdf

A longer run is the same command with -n set above the default of 2500. This note does not record a specific step count, so there is no third command to copy.

The output is a ligand that is less likely to explode in docking or in the first steps of MD. It is still a force-field minimum of the free ligand, not a bound conformation and not a quantum geometry.

Last updated on Jan 12, 2024