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Force Field Selection Tutorial

Quick Start

prism protein.pdb ligand.mol2 -o gaff_system --ligand-forcefield gaff
prism protein.pdb ligand.sdf -o openff_system --ligand-forcefield openff

Overview

Learn how to select and compare different force fields for your protein-ligand system using PRISM's support for 8+ ligand parameterization methods.

Time: 45-90 minutes Level: Intermediate

Prerequisites

  • Completed Basic Tutorial
  • PRISM with force field dependencies installed
  • Understanding of force field concepts

Force Fields Covered

This tutorial demonstrates:

  • GAFF - General AMBER Force Field
  • GAFF2 - Improved GAFF
  • OpenFF - Open Force Field
  • OPLS-AA - Using LigParGen

Step 1: Prepare the System

mkdir ff_comparison
cd ff_comparison

# Use same inputs as basic tutorial
wget https://files.rcsb.org/download/3DMX.pdb -O protein.pdb
wget https://github.com/AIB001/PRISM-tutorial-data/raw/main/basic/benzene.mol2

Step 2: Build with Different Force Fields

GAFF (Default)

prism protein.pdb benzene.mol2 -o gaff_system --ligand-forcefield gaff

GAFF2

prism protein.pdb benzene.mol2 -o gaff2_system --ligand-forcefield gaff2

OpenFF

prism protein.pdb benzene.mol2 -o openff_system --ligand-forcefield openff

OPLS-AA

prism protein.pdb benzene.mol2 -o opls_system --ligand-forcefield opls

Step 3: Run Simulations

# Run all systems (can be parallelized)
for system in gaff_system gaff2_system openff_system opls_system; do
    cd $system/GMX_PROLIG_MD
    bash localrun.sh &
    cd ../..
done

Step 4: Compare Results

Binding Stability

import prism as pm
import matplotlib.pyplot as plt
import numpy as np

force_fields = ['gaff', 'gaff2', 'openff', 'opls']
results = {}

for ff in force_fields:
    analysis = pm.analyze_trajectory(
        f"{ff}_system/GMX_PROLIG_MD/system.gro",
        f"{ff}_system/GMX_PROLIG_MD/prod/md.xtc",
        ligand_resname="BEN",
        output_dir=f"{ff}_analysis"
    )
    results[ff] = analysis

# Compare RMSD, contacts, etc.
print("Force Field Comparison:")
for ff in force_fields:
    print(f"{ff.upper()}: {results[ff]['summary']}")

Step 5: Interpret Differences

Compare force fields based on:

  1. Charge Assignment
  2. Check partial charges in topology files

  3. Different methods yield different charges

  4. Binding Stability

  5. Which FF keeps ligand most stable?

  6. RMSD fluctuations

  7. Interaction Patterns

  8. Hydrogen bonding differences
  9. Hydrophobic contacts

Recommendations

  • GAFF/GAFF2: Good default, widely tested
  • OpenFF: More accurate for drug-like molecules
  • OPLS-AA: Excellent for aromatic systems
  • CGenFF: Best for CHARMM protein FF

What's Next