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Tips for force field selection in 3D optimization

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HiroYokoyama edited this page Oct 30, 2025 · 4 revisions

Force Field Selection: MMFF (94/94s) vs. UFF

For 3D structure "Re-optimization (Cleanup)," you must select a "Force Field" to calculate the molecule's energy. Force fields differ significantly in their intended purpose and, crucially, their elemental coverage.

Overview: MMFF vs. UFF

Feature MMFF (Merck Molecular Force Field) UFF (Universal Force Field)
Primary Goal High-accuracy structure/energy for organic & medicinal molecules. General-purpose estimation for any molecule.
Supported Elements Common organic elements (C, H, N, O, F, Si, P, S, Cl, Br, I) and some ions (Na+, K+, Zn2+, etc.). Most metals are not supported. Nearly the entire periodic table (H to Lr, elements 1-103).
Accuracy Very high accuracy for molecules within its parameter set (i.e., organic molecules). General-purpose. Can handle organometallics but is less accurate than MMFF for organics.

💊 MMFF (Merck Molecular Force Field)

  • Description:
    • Developed by the Merck pharmaceutical company specifically for drug design.
    • Parameters are rigorously tuned using a vast set of organic molecules to accurately reproduce high-level quantum chemistry calculations and experimental data.
  • Pros:
    • Provides extremely high-accuracy structures and relative energies for organic and medicinal molecules composed of its supported elements (esp. C, H, N, O, P, S, and halogens).
  • Cons:
    • Supported elements are limited. It cannot be used for molecules containing most metals or other unsupported elements.

The Difference Between "94" and "94s"

MMFF94 and MMFF94s use the same core MMFF parameter set but have a subtle difference:

  • MMFF94:
    • The full, validated version. It is designed to accurately evaluate molecular energies and conformations.
    • In some cases (e.g., the -NH2 group in aniline), it may correctly calculate a slightly more stable "pyramidal" (non-planar) structure.
  • MMFF94s:
    • The "s" often stands for "static."
    • This is a modified version designed to be more robust (i.e., less likely to fail) during minimizations, especially for tasks like docking.
    • It simplifies or constrains certain structures. For example, it forces nitrogen atoms in amide bonds or attached to aromatic rings to be treated as "planar."
    • For general-purpose structure optimization or cleanup, MMFF94s is often preferred as it tends to produce chemically intuitive structures (like planar amides).

🧪 UFF (Universal Force Field)

  • Description:
    • As its "Universal" name implies, its greatest strength is its coverage of nearly the entire periodic table.
    • Parameters are generated automatically based on general properties for each element (atomic radius, ionization potential, hybridization, etc.).
  • Pros:
    • Often the only choice for optimizing structures that MMFF does not support, such as metal complexes, inorganic compounds, and organometallics.
  • Cons:
    • Because the parameters are general, its accuracy for common organic molecules (especially conformational energy differences) is generally lower than that of the highly-tuned MMFF.

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