Molecular Dynamics

uv venv --python 3.12 .venv-md
uv pip install --python .venv-md/bin/python "openmm==8.6.1" "MDAnalysis==2.10.0" matplotlib pandas
# Windows: use .venv-md/Scripts/python.exe instead

from openmm.app import *
from openmm import *
from openmm.unit import *

def prepare_system_from_pdb(pdb_file, forcefield_name="amber14-all.xml",
                              water_model="amber14/tip3pfb.xml", ph=7.0):
    """
    Prepare an OpenMM system from a PDB file.

    Args:
        pdb_file: Path to cleaned PDB file (use PDBFixer for raw PDB files)
        forcefield_name: Force field XML file
        water_model: Water model XML file

    Returns:
        modeller, system
    """
    # Load PDB
    pdb = PDBFile(pdb_file)

    # Load force field
    forcefield = ForceField(forcefield_name, water_model)

    # Add hydrogens and solvate
    modeller = Modeller(pdb.topology, pdb.positions)
    modeller.addHydrogens(forcefield, pH=ph)

    # TIP3P geometry also serves TIP3P-FB; XML supplies the parameters.
    # 10 Å padding; added salt excludes neutralizing counterions.
    modeller.addSolvent(
        forcefield,
        model='tip3p',
        padding=10*angstroms,
        ionicStrength=0.15*molar, neutralize=True
    )

    print(f"System: {modeller.topology.getNumAtoms()} atoms, "
          f"{modeller.topology.getNumResidues()} residues")

    # Create system
    system = forcefield.createSystem(
        modeller.topology,
        nonbondedMethod=PME,         # Particle Mesh Ewald for long-range electrostatics
        nonbondedCutoff=1.0*nanometer,
        constraints=HBonds,           # Constrain bonds involving H (not intermolecular H-bonds)
        rigidWater=True,
        ewaldErrorTolerance=0.0005
    )

    return modeller, system

from openmm.app import *
from openmm import *
from openmm.unit import *

def minimize_energy(modeller, system, output_pdb="minimized.pdb",
                     max_iterations=1000, tolerance=10.0, platform_name=None):
    """
    Energy minimize the system to remove steric clashes.

    Args:
        modeller: Modeller object with topology and positions
        system: OpenMM System
        output_pdb: Path to save minimized structure
        max_iterations: Maximum minimization steps
        tolerance: Convergence criterion in kJ/mol/nm

    Returns:
        simulation object with minimized positions
    """
    # Keep the integrator at 2 fs for the subsequent NVT/NPT examples.
    integrator = LangevinMiddleIntegrator(300*kelvin, 1/picosecond, 0.002*picoseconds)

    # Automatic platform selection, or an explicit tested platform (e.g. CPU).
    # A registered GPU plugin does not prove a working device or driver.
    platform = Platform.getPlatformByName(platform_name) if platform_name else None
    simulation = Simulation(modeller.topology, system, integrator, platform)
    simulation.context.setPositions(modeller.positions)

    # Check initial energy
    state = simulation.context.getState(getEnergy=True)
    print(f"Initial energy: {state.getPotentialEnergy()}")

    # Minimize
    simulation.minimizeEnergy(
        tolerance=tolerance*kilojoules_per_mole/nanometer,
        maxIterations=max_iterations
    )

    state = simulation.context.getState(getEnergy=True, getPositions=True)
    print(f"Minimized energy: {state.getPotentialEnergy()}")

    # Save minimized structure
    with open(output_pdb, 'w') as f:
        PDBFile.writeFile(simulation.topology, state.getPositions(), f)

    return simulation

from openmm.app import *
from openmm import *
from openmm.unit import *

def run_nvt_equilibration(simulation, n_steps=50000, temperature=300,
                            report_interval=1000, output_prefix="nvt"):
    """
    NVT equilibration: constant N, V, T.
    Equilibrate velocities to target temperature.

    Args:
        simulation: OpenMM Simulation (after minimization)
        n_steps: Number of MD steps (50000 × 2fs = 100 ps)
        temperature: Temperature in Kelvin
        report_interval: Steps between data reports
        output_prefix: File prefix for trajectory and log
    """
    # This example is unrestrained; add validated restraints before Context creation.
    if any("Barostat" in type(f).__name__ and f.getFrequency() > 0
           for f in simulation.system.getForces()):
        raise ValueError("NVT requires all barostats disabled or absent")

    # Set both the thermostat target and initial velocities.
    simulation.integrator.setTemperature(temperature*kelvin)
    simulation.context.setVelocitiesToTemperature(temperature*kelvin)

    # Add reporters
    simulation.reporters = []

    # Log file
    simulation.reporters.append(
        StateDataReporter(
            f"{output_prefix}_log.txt",
            report_interval,
            step=True,
            potentialEnergy=True,
            kineticEnergy=True,
            temperature=True,
            volume=True,
            speed=True
        )
    )

    # DCD trajectory (compact binary format)
    simulation.reporters.append(
        DCDReporter(f"{output_prefix}_traj.dcd", report_interval)
    )

    duration = (n_steps * simulation.integrator.getStepSize()).value_in_unit(picoseconds)
    print(f"Running NVT equilibration: {n_steps} steps ({duration:.1f} ps)")
    simulation.step(n_steps)
    print("NVT equilibration complete")

    return simulation

def run_npt_production(simulation, n_steps=500000, temperature=300, pressure=1.0,
                        report_interval=5000, output_prefix="npt"):
    """
    NPT production run: constant N, P, T.

    Args:
        n_steps: Production steps (500000 × 2fs = 1 ns)
        temperature: Temperature in Kelvin
        pressure: Pressure in bar
        report_interval: Steps between reports
    """
    # Keep the Langevin thermostat and barostat at the same temperature.
    simulation.integrator.setTemperature(temperature*kelvin)
    system = simulation.system
    barostats = [f for f in system.getForces() if "Barostat" in type(f).__name__]
    if not system.usesPeriodicBoundaryConditions():
        raise ValueError("NPT requires a periodic system")
    if not barostats:
        system.addForce(MonteCarloBarostat(pressure*bar, temperature*kelvin, 25))
        simulation.context.reinitialize(preserveState=True)
    elif len(barostats) != 1 or not isinstance(barostats[0], MonteCarloBarostat):
        raise ValueError("This example supports one isotropic MonteCarloBarostat")
    else:
        barostats[0].setDefaultPressure(pressure*bar)
        barostats[0].setDefaultTemperature(temperature*kelvin)
        barostats[0].setFrequency(25)
    # Existing Context parameters must also be updated on repeated calls.
    simulation.context.setParameter(MonteCarloBarostat.Pressure(), pressure)
    simulation.context.setParameter(MonteCarloBarostat.Temperature(), temperature)

    # Update reporters
    simulation.reporters = []
    simulation.reporters.append(
        StateDataReporter(
            f"{output_prefix}_log.txt",
            report_interval,
            step=True,
            potentialEnergy=True,
            temperature=True,
            density=True,
            speed=True
        )
    )
    simulation.reporters.append(
        DCDReporter(f"{output_prefix}_traj.dcd", report_interval)
    )

    # Save checkpoints
    simulation.reporters.append(
        CheckpointReporter(f"{output_prefix}_checkpoint.chk", 50000)
    )

    duration = (n_steps * simulation.integrator.getStepSize()).value_in_unit(nanoseconds)
    print(f"Running NPT stage: {n_steps} steps ({duration:.3f} ns)")
    simulation.step(n_steps)
    simulation.saveCheckpoint(f"{output_prefix}_checkpoint.chk")
    simulation.saveState(f"{output_prefix}_state.xml")
    print("NPT stage complete")
    return simulation

import MDAnalysis as mda
from MDAnalysis.analysis import rms, align, contacts
import numpy as np
import matplotlib.pyplot as plt

def load_trajectory(topology_file, trajectory_file):
    """
    Load an MD trajectory with MDAnalysis.

    Args:
        topology_file: PDB, PSF, or other topology file
        trajectory_file: DCD, XTC, TRR, or other trajectory
    """
    u = mda.Universe(topology_file, trajectory_file)
    print(f"Universe: {u.atoms.n_atoms} atoms, {u.trajectory.n_frames} frames")
    first, last = u.trajectory[0].time, u.trajectory[-1].time
    print(f"Time range: {first:g} to {last:g} ps")
    u.trajectory[0]
    return u

def compute_rmsd(u, selection="backbone", reference_frame=0):
    """
    Compute RMSD of selected atoms relative to reference frame.

    Args:
        u: MDAnalysis Universe
        selection: Atom selection string (MDAnalysis syntax)
        reference_frame: Frame index for reference structure

    Returns:
        numpy array with columns [frame index, time in ps, RMSD in Angstroms]
    """
    # RMSD performs its own fit; avoid rotating the stored trajectory here.
    # Make the selected molecule whole before analysis of periodic trajectories.
    R = rms.RMSD(u, select=selection, ref_frame=reference_frame)
    R.run()

    rmsd_data = R.results.rmsd  # columns: frame, time, RMSD
    return rmsd_data

def plot_rmsd(rmsd_data, title="RMSD over time", output_file="rmsd.png"):
    """Plot RMSD over simulation time."""
    fig, ax = plt.subplots(figsize=(10, 4))
    ax.plot(rmsd_data[:, 1] / 1000, rmsd_data[:, 2], 'b-', linewidth=0.5)
    ax.set_xlabel("Time (ns)")
    ax.set_ylabel("RMSD (Å)")
    ax.set_title(title)
    ax.axhline(rmsd_data[:, 2].mean(), color='r', linestyle='--',
               label=f'Mean: {rmsd_data[:, 2].mean():.2f} Å')
    ax.legend()
    plt.tight_layout()
    plt.savefig(output_file, dpi=150)
    return fig

def compute_rmsf(u, selection="protein and name CA", start_frame=0):
    """
    Compute per-residue RMSF (flexibility).

    Returns:
        residue_keys, rmsf_values; keys are (resindex, segid, resid, resname)
    """
    # Select atoms
    atoms = u.select_atoms(selection)

    if not len(atoms):
        raise ValueError("RMSF selection is empty")
    # A multi-atom selection returns mean atomic RMSF, not COM RMSF.
    R = rms.RMSF(atoms)
    R.run(start=start_frame)

    # Average by residue
    resids = []
    rmsf_per_res = []
    for res in u.select_atoms(selection).residues:
        res_atoms = res.atoms.intersection(atoms)
        if len(res_atoms) > 0:
            resids.append((res.ix, res.segid, res.resid, res.resname))
            # RMSF is indexed within the selected AtomGroup, not the Universe.
            rmsf_per_res.append(R.results.rmsf[atoms.resindices == res.ix].mean())

    return resids, np.array(rmsf_per_res)

def analyze_contacts(u, protein_sel="protein", ligand_sel="resname LIG",
                      radius=4.5, start_frame=0, periodic=True):
    """
    Track protein-ligand contacts over trajectory.

    Args:
        radius: Atom-pair cutoff in Angstroms; any pair defines a residue contact.
        periodic: Require box data and use minimum-image distances.
    Returns sets of (resindex, segid, resid, resname), one per analyzed frame.
    """
    from MDAnalysis.lib.distances import distance_array

    protein = u.select_atoms(protein_sel)
    ligand = u.select_atoms(ligand_sel)

    if not len(protein) or not len(ligand):
        raise ValueError("Protein and ligand selections must both be nonempty")
    if not np.isfinite(radius) or radius <= 0:
        raise ValueError("radius must be finite and positive")
    contact_frames = []
    for ts in u.trajectory[start_frame:]:
        if periodic and (ts.dimensions is None or not np.all(np.isfinite(ts.dimensions))
                         or np.any(ts.dimensions[:3] <= 0)):
            raise ValueError("Periodic contacts require valid frame box dimensions")
        # This includes hydrogen atoms unless the caller selects heavy atoms.
        distances = contacts.contact_matrix(
            distance_array(protein.positions, ligand.positions, box=ts.dimensions if periodic else None),
            radius,
        )
        contact_residues = set()
        for i in range(distances.shape[0]):
            if distances[i].any():
                res = protein[i].residue
                contact_residues.add((res.ix, res.segid, res.resid, res.resname))
        contact_frames.append(contact_residues)

    return contact_frames