A force-field setup can fail before a simulation even begins—or appear to succeed while leaving warnings that are easy to overlook. Often the problem is not the choice between Amber, CHARMM, or OpenFF. It is a mismatch between the structure in the document, the atoms the setup is meant to cover, and the parameters available for those atoms.
A useful way to troubleshoot is to work from the target outward: first check what atoms SAMSON is being asked to parameterize, then check whether the structure is ready, and only then adjust the force-field setup. This avoids repeatedly changing presets without addressing the underlying issue.
1. Confirm what the simulator will target
Before choosing a force field, confirm that the intended molecular system is loaded in the active document. If the simulator should act on only part of the document, select the relevant atoms. This matters especially in Composite and Advanced workflows, where an atom-group query determines which parameters are applied to which atoms.
For a single-force-field system, start with Standard. It is the typical workflow for proteins, DNA, RNA, water, ions, or a small organic molecule. A protein–ligand complex that needs separate biomolecule and ligand parameterization usually calls for Composite. Use Advanced when you need to assign files to multiple atom groups or use custom force-field files.
2. Treat structure preparation as part of parameterization
Amber and CHARMM typing can be disrupted by structural details that are easy to miss when looking at a molecular model. Before trying those workflows, check for alternate locations imported together, missing hydrogens, uncertain protonation states, incomplete fragments, and unsupported heterogens such as ligands, cofactors, additives, or buffer molecules.
Also check that waters and ions are compatible with the selected water / ion model, and look for accidental covalent bonds between components that should be separate. These checks are more productive than switching force fields at random: a different preset does not necessarily resolve a malformed or unsupported target.
3. Make the ligand selection precise
In Composite mode, the protein and ligand are handled separately: the protein uses an Amber or CHARMM preset, while the ligand can use Sage or Parsley. Assign ligand atoms to the NSL class lig, then refresh the ligand query and check the reported atom count for n.c lig.
The query should select the ligand atoms—and only those atoms. If it selects none or every atom in the document, the composite setup cannot be created. Composite mode also requires at least one protein atom outside the ligand selection and does not support covalent bonds between protein and ligand atoms. If the ligand is covalently attached, the setup needs a force field that represents that covalent chemistry directly.
4. Use Advanced mode deliberately
Advanced mode gives each group an NSL query and a list of force-field files. Explicit groups are evaluated in order, so earlier groups take priority; the default * group handles atoms not matched earlier. This means group order is part of the setup, not just a display preference. Check that each query selects the intended atoms and watch for diagnostics indicating that a group matches no atoms or that its atoms were already assigned.
There is also an important file-compatibility rule: files within one group must all be XML or all be OFFXML. If different parts of a system need different file families, put them in separate groups. Custom .xml and .offxml files can be added, but a custom file may still contain constructs the extension does not support.
5. Read the status before pressing OK
The setup window checks the selected force field against the current target, and OK is enabled only when the current setup can be used. If force-field choices are missing, use the reload button to install or update the local bundles; this is needed only when bundles are missing or you want to update them.
Once the interaction model is created, inspect its properties rather than relying on a single energy value. Confirm the provider and parameter set, check whether the model is constrained, and review generated terms, atom types, per-atom parameters, warnings, and status. A ready setup means the target can be parameterized by that configuration; it does not replace reviewing warnings or checking that the model matches your scientific intent.
For routine interactive work and minimization, the documentation recommends Constrained. Choose Unconstrained only when you need X–H bond flexibility to be preserved. After creating the model, start the simulation and allow the first energy and force evaluation to finish before interpreting the results.
For the full setup instructions, see the Molecular Mechanics Force Fields tutorial.
Note: SAMSON and all SAMSON Extensions are free for non-commercial use. Get SAMSON.