Understanding Charge and Stereochemistry Handling in GINGER Conformer Generation

[Andrew Orry]

Before running GINGER to generate 3D conformers in .molt format, it’s helpful to understand how the tool handles formal charges, stereochemistry, and double bond configurations. The following Q&A addresses common questions about preparing molecular input and interpreting GINGER's behavior under various scenarios.

Q1: Do formal charge assignment and stereochemistry enumeration need to be done prior to running GINGER to generate conformers (.molt file)?
A:
Not necessarily — it depends on your input and goals:

• Formal Charges:
  If your input molecules already have formal charges assigned and you want to preserve them, no additional steps are needed.
  If the charges are missing or incomplete, use the -Cn option (see Q2 below) to have GINGER assign formal charges automatically.

• Stereochemistry:
  GINGER preserves defined stereocenters as-is. For undefined (racemic) centers, GINGER samples stereoisomers during conformer generation (see Q3 below). However, the number of conformers per stereoisomer will be limited, since the total number of conformers is divided across all possible stereoisomers.
  For better coverage — especially for molecules with multiple racemic centers — it's recommended to enumerate stereoisomers beforehand. This way, GINGER will generate a full set of conformers for each defined stereoisomer individually.

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Q2: Can GINGER assign charges automatically, and what models are available?
A:
Yes. GINGER can assign formal charges automatically based on predicted protonation states:

• Use the -C option to apply MolSoft’s standard pKa-based model.

• Use the -Cn option (in newer versions) to apply a neural network-assisted pKa model, which may provide improved accuracy in some cases.

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Q3: What is the behavior of GINGER when a racemic chiral center is present? Are N conformers generated per enantiomer or in total?
A:
GINGER will generate up to N conformers total. For each conformer, random stereochemistry is assigned at racemic centers.
For example, if there is one racemic center and N = 30, the output typically includes approximately 15 conformers for each enantiomer, depending on sampling randomness.

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Q4: How does GINGER handle double bonds when no cis/trans specification is given?
A:
If the input does not restrict double bond configuration (e.g., unspecified in SMILES), GINGER will generate a mixture of cis and trans conformers within the total N limit.
The distribution depends on the chemical environment and training statistics — sometimes near-equal, sometimes skewed toward one isomer.