Monte Carlo for Proteins
Monte Carlo simulations of peptides, proteins, and nucleic acids in explicit solvent. Derived from BOSS with extensive biomolecular extensions, MCPRO is the primary tool for computing protein-ligand binding free energies using statistical perturbation theory.
MCPRO extends BOSS to biomolecular systems — peptides, proteins, and nucleic acids simulated in explicit aqueous solvent. It is the workhorse of the Jorgensen group's drug discovery pipeline, used to compute protein-ligand binding free energies with accuracy that rivals much more expensive methods. The key innovation is the use of Z-matrix internal coordinate moves that efficiently sample conformational space of the solute while treating the protein environment with full atomic detail.
Protein-Ligand Binding
Free energy perturbation calculations for relative binding affinities between ligand analogues. Alchemical mutation of one ligand to another within the protein active site using double-wide FEP sampling.
Explicit Solvent Simulation
Periodic box simulation with TIP3P or TIP4P water. Full treatment of solvent structure around the protein and ligand. Residue-based cutoffs for efficient energy evaluation in large systems.
Z-Matrix Sampling
Internal coordinate Monte Carlo moves using Z-matrix representation for the solute. Efficient sampling of ligand and protein side-chain degrees of freedom without the overhead of Cartesian MD.
OPLS-AA/L Force Field
Validated protein backbone and side-chain parameters from OPLS-AA/L, with improved dihedral terms for accurate secondary structure reproduction. Full OPLS-AA coverage for small-molecule ligands.
Energy Decomposition
Residue-by-residue breakdown of protein-ligand interaction energies. Identifies key binding contacts and hotspot residues, guiding medicinal chemistry optimisation decisions.
Biomolecular Sampling
Peptide and protein conformational sampling in solution. Loop modelling, side-chain rotamer sampling, and ligand binding mode exploration within full protein contexts.
Protein-Ligand Free Energy Perturbation
Relative binding free energy calculations via statistical perturbation theory. The ligand is alchemically mutated from one analogue to another in both the protein-bound and aqueous states; ΔΔG binding is obtained from the thermodynamic cycle. Double-wide sampling collects both forward and reverse perturbation data simultaneously for improved convergence. Supports multi-step perturbation paths with configurable window counts.
Z-Matrix Monte Carlo Moves
Solute conformational sampling using internal (Z-matrix) coordinates rather than Cartesian displacements. Bond lengths, bond angles, and dihedral angles are moved independently with configurable acceptance windows. Preferential sampling weights solute-solvent interactions to accelerate convergence of solvation properties. Protein backbone and side-chain moves use residue-specific Z-matrix definitions.
OPLS-AA/L Force Field for Proteins
The OPLS-AA/L parameter set provides improved backbone dihedral terms fitted to high-level QM data on alanine and glycine dipeptides, correcting the over-stabilisation of helical conformations present in early OPLS-AA. Side-chain parameters are unchanged from OPLS-AA. Ligand parameters derived from OPLS-AA with RESP partial charges from AM1-BCC. Covers all 20 standard amino acids, common post-translational modifications, and nucleic acid residues.
Explicit and Implicit Solvent Models
Explicit water models: TIP3P (default for protein simulations), TIP4P. Periodic boundary conditions with minimum image convention. Residue-based cutoff scheme (typically 10–12 Å) for non-bonded interactions. Long-range electrostatics via reaction field correction. Implicit solvent option using GB/SA for rapid relative free energy estimates when explicit solvent convergence is prohibitive.
Residue-Based Cutoffs and Neighbour Lists
Non-bonded interactions evaluated using residue-based cutoffs rather than atom-based, reducing the frequency of neighbour list updates and improving performance for large protein systems. Solute-solvent and solvent-solvent interactions separated with independent cutoff distances. Efficient memory layout for systems of 1,000–10,000 atoms typical in protein-ligand FEP calculations.
Interaction Energy Decomposition
Per-residue decomposition of protein-ligand non-bonded interaction energies (Lennard-Jones + electrostatic). Identifies key contacts and quantifies their contribution to binding. Solute-solvent energy decomposition shows which portions of the ligand are well or poorly solvated. Output in tabular CSV format for direct import into visualisation and analysis tools.
What MCPRO reads
Protein structure (.pdb)
Prepared protein structure with hydrogens, correct protonation states, and any co-crystallised waters. Standard PDB format; pre-processed through the MCPRO structure preparation utilities.
Ligand Z-matrix (.z)
Internal coordinate description of the ligand with OPLS atom types and partial charges. Generated from PDB or MOL2 input using the integrated Z-matrix builder.
Ligand structures (.mol2 / .sdf)
Small-molecule input formats for automatic Z-matrix generation. Partial charges assigned via AM1-BCC. Supports series of analogues for FEP campaigns.
Custom parameter files (.par)
User-defined OPLS parameters for non-standard residues, modified amino acids, or novel ligand functional groups not covered by the standard library.
Simulation control file
Defines ensemble, step count, cutoffs, FEP windows, output frequency, and all simulation parameters. Set through the platform's guided input interface.
What MCPRO returns
Relative binding free energies
ΔΔG binding values with bootstrap uncertainties, forward/reverse free energy estimates, and hysteresis as a convergence metric. CSV and summary report formats.
Residue interaction decomposition
Per-residue LJ and electrostatic contributions to the ligand binding energy. Heatmap visualisation available in the platform's analysis dashboard.
Simulation trajectories (.pdb)
Coordinate snapshots of protein-ligand complex at user-defined intervals. Viewable in the 3D visualisation suite with binding mode overlay tools.
Radial distribution functions
Solute-solvent pair distribution functions and coordination numbers. H-bond occupancies between ligand and active site residues across the trajectory.
Full calculation log
Complete record of all parameters, convergence diagnostics, per-window averages, and statistical analysis. Downloadable for archiving and methods sections.
Molecular Modeling of Organic and Biomolecular Systems Using BOSS and MCPRO
Journal of Computational Chemistry · 2005 · Vol. 26, pp. 1689–1700
Jorgensen, W. L.; Tirado-Rives, J. "Molecular Modeling of Organic and Biomolecular Systems Using BOSS and MCPRO." J. Comput. Chem. 2005, 26, 1689–1700.
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