QMMESP - QM/MM Environment-aware RESP Charge Derivation

A Python script for computing environment-aware RESP charges of ligands using QM/MM calculations with electrostatic embedding. The script supports both ORCA and PySCF as quantum mechanics engines and uses Multiwfn for RESP charge fitting.

Overview
Features
Installation
Dependencies
Usage
Input Files
Output Files
Examples
Citation
License

Overview

QMMESP calculates RESP (Restrained Electrostatic Potential) charges for ligands while considering their local protein environment through QM/MM calculations. Unlike traditional gas-phase RESP calculations, this approach:

Includes environmental effects: The ligand is treated quantum mechanically while the protein environment is modeled with classical force fields
Uses electrostatic embedding: Point charges from the MM region polarize the QM wavefunction
Supports multiple QM engines: Choose between PySCF (default) or ORCA for quantum calculations
Automated workflow: From prepared MD structures to final RESP charges in one step

Features

✅ Dual QM Engine Support: PySCF (default) or ORCA
✅ Environment-aware Charges: QM/MM approach includes protein effects
✅ AMBER Integration: Direct prepi file updates for MD simulations

Installation

1. Clone the Repository

git clone https://github.com/miqueleg/QMMESP.git
cd QMMESP

2. Set Up Python Environment

#Create conda environment
conda create -n qmmesp python=3.11
conda activate qmmesp

#Install required packages
pip install numpy mdtraj

3. Install Dependencies

| Software | Purpose | Installation | |----------|---------|-------------| | ASH | QM/MM calculations | python -m pip install git+https://github.com/RagnarB83/ash.git | | PySCF | QM engine (default) | pip install --prefer-binary pyscf | | ORCA | QM engine (optional) | Download from ORCA website | | Multiwfn | RESP fitting | Download from Multiwfn website | | OpenMM | MM calculations | conda install -c conda-forge openmm |

Environment Variables

#Add to your ~/.bashrc or ~/.zshrc
export Multiwfnpath="/path/to/multiwfn"
export ORCADIR="/path/to/orca" # Only if using ORCA

Usage

Basic Command

python QMMESP.py --pdb complex.pdb --prmtop complex.prmtop --inpcrd complex.inpcrd --resid 1

Complete Example

python QMMESP.py
--pdb solvated_complex.pdb
--prmtop complex.prmtop
--inpcrd complex.inpcrd
--prepi ligand.prepi
--resid 285
--charge 0
--functional HF
--basis 6-31G*
--qm_engine pyscf
--output resp_results
--numcores 4

Command Line Arguments

| Argument | Required | Default | Description | |----------|----------|---------|-------------| | --pdb | ✅ | - | Input PDB file (solvated complex) | | --prmtop | ✅ | - | AMBER topology file | | --inpcrd | ✅ | - | AMBER coordinate file | | --resid | ✅ | - | Residue ID of the ligand | | --prepi | ❌ | - | Original prepi file for charge updates | | --charge | ❌ | 0 | Net charge of the QM region | | --mult | ❌ | 1 | Multiplicity of the QM region | | --functional | ❌ | HF | DFT functional (HF, B3LYP, PW6B95, etc.) | | --basis | ❌ | 6-31G* | Basis set | | --qm_engine | ❌ | pyscf | QM engine: pyscf or orca | | --output | ❌ | qmmm_resp | Output directory | | --numcores | ❌ | 8 | Number of CPU cores | | --multiwfnpath | ❌ | $Multiwfnpath | Path to Multiwfn installation | | --orcadir | ❌ | $ORCADIR | Path to ORCA installation |

Input Files

Required Files

PDB File (--pdb): Solvated protein-ligand complex
- Must contain properly numbered residues
- Ligand should have a unique residue name
- Can include crystallographic waters
Topology File (--prmtop): AMBER parameter/topology file
- Generated using tleap with appropriate force fields
- Must include parameters for all system components
Coordinate File (--inpcrd): AMBER coordinate file
- Matching the topology file
- Typically from energy minimization or equilibration

Optional Files

Prepi File (--prepi): AMBER residue library file
- Will be updated with new RESP charges
- Useful for subsequent MD simulations

Output Files

Generated Files

| File | Description | |------|-------------| | substrate_[engine]_charges.txt | RESP charges for each atom | | esp.molden | Molecular orbital file for ESP analysis | | [residue]_[engine].prepi | Updated prepi file with RESP charges | | multiwfn.log | Multiwfn calculation log | | multiwfn_input.txt | Input file for Multiwfn | | esp.chg | Raw charge data from Multiwfn |

Examples

Example 1: Basic RESP Calculation with PySCF

python QMMESP.py
--pdb protein_ligand.pdb
--prmtop system.prmtop
--inpcrd system.inpcrd
--resid 500
--charge -1

Example 2: High-Level RESP2-like Charges with ORCA

python QMMESP.py
--pdb complex_solvated.pdb
--prmtop complex.prmtop
--inpcrd complex.inpcrd
--resid 285
--functional PW6B95
--basis aug-cc-pVDZ
--qm_engine orca
--numcores 16
--output resp2_results

Example 3: Update Prepi File for MD

python QMMESP.py
--pdb equilibrated.pdb
--prmtop system.prmtop
--inpcrd system.inpcrd
--prepi original_ligand.prepi
--resid 1
--functional B3LYP
--basis 6-31G*
--output updated_params

Performance Tips

Use PySCF for routine calculations: Generally faster and more stable
Optimize core usage: Start with 4-8 cores, increase for large systems
Monitor memory usage: Large basis sets may require significant RAM
Use recomended basis sets: HF/6-31G* for ff14SB, PW6B95/aug-cc-pVDZ for ff19SB

Method Details

QM/MM Setup

QM Region: Ligand of interest (specified by residue ID)
MM Region: Protein, water, and ions
Embedding: Electrostatic (point charges polarize QM wavefunction)
Boundary: Automatic detection based on residue boundaries

RESP Fitting

ESP Generation: Quantum mechanical electrostatic potential on molecular surface
Grid Points: Multiwfn automatically generates fitting points
Restraints: Standard RESP restraints applied (0.0005 au for C,N,O,S; 0.001 au for H)
Fitting: Two-stage RESP procedure with buried carbon restraints

Recommended Methods

| Purpose | Functional | Basis Set | Notes | |---------|------------|-----------|--------| | RESP1-like | HF | 6-31G* | Traditional RESP charges | | RESP2-like | PW6B95 | aug-cc-pVDZ | Modern improved method |

Citation

If you use this software in your research, please cite:

@software{qmmesp2025,
author = {Miquel Estévez-Gay},
title = {QMMESP: Environment-aware RESP charge derivation using QM/MM},
url = {https://github.com/miqueleg/QMMESP},
year = {2025}
}

Related Publications

Bayly, C. I.; Cieplak, P.; Cornell, W.; Kollman, P. A. J. Phys. Chem. 1993, 97, 10269-10280. (Original RESP method)
Schauperl, M.; Nerenberg, P. S.; Jang, H.; et al. J. Chem. Theory Comput. 2020, 16, 7044-7060. (RESP2 method)

Contributing

Contributions are welcome! Please feel free to submit a Pull Request. For major changes, please open an issue first to discuss what you would like to change.

License

This project is licensed under the MIT License - see the LICENSE file for details.

Support

For questions, issues, or suggestions:

GitHub Issues: Create an issue
ORCA Forum: For ORCA-specific questions
PySCF Community: For PySCF-related issues
ASH GitHub: For ASH-related issues

Note: This software is provided as-is for research purposes. Always validate results against experimental data or established benchmarks for your specific systems.

QMMESP

Install / Use

README