From a4f63be7da85d554c01082d775f8656df8638e09 Mon Sep 17 00:00:00 2001
From: JaktensTid <jaktenstid1@gmail.com>
Date: Sun, 3 Dec 2023 17:49:16 +0300
Subject: [PATCH] Adding conformations ui

---
 src/server/api_handlers/conformations.py      |  28 +-
 src/server/frontend/src/storage.js            |   1 +
 .../src/views/ConformationsFormView.vue       | 104 ++++-
 .../frontend/src/views/ConformationsLab.vue   |   2 +-
 .../conformations/conformations_pipeline.py   | 441 ++++++++++--------
 5 files changed, 371 insertions(+), 205 deletions(-)

diff --git a/src/server/api_handlers/conformations.py b/src/server/api_handlers/conformations.py
index 296071c8..75127fd4 100644
--- a/src/server/api_handlers/conformations.py
+++ b/src/server/api_handlers/conformations.py
@@ -1,6 +1,6 @@
 from flask import Request
 
-#from src.server.services.conformations.conformations_pipeline import permute_simulation
+from src.server.services.conformations.conformations_pipeline import pipeline
 from src.server.services.experiments_structure_loader import ConformationsExperimentsLoader
 from src.server.api_handlers.api_handler import ApiHandler
 
@@ -41,9 +41,28 @@ def inference(self, request: Request) -> dict:
         protein_files = request.files.getlist('proteinFileInput')
         experiment_name = request.form['experimentName']
         experiment_id = request.form['experimentId']
+        total_frames = int(request.form['totalFramesInput'])
+        system_temp = float(request.form['tempInput'])
+        take_frame_every = int(request.form['takeFrameEveryInput'])
+        step_size = float(request.form['stepSizeInput'])
+        replace_nonstandard_residues = True if request.form['replaceNonstandardResiduesInput'] == 'on' else False
+        integrator = request.form['integratorSelect']
+        friction_coeff = float(request.form['frictionCoeffInput'])
+        add_missing_hydrogens = True if request.form['addMissingHydrogensCheckbox'] == 'on' else False
+        add_missing_atoms = True if request.form['addMissingAtomsCheckbox'] == 'on' else False
+        ignore_missing_atoms = True if request.form['ignoreMissingAtomsCheckbox'] == 'on' else False
 
-        #simulation_result = permute_simulation(protein_files[0])
-        simulation_result = ''
+        (simulation_result, errors) = pipeline(pdb_content=protein_files[0],
+                                     total_frames=total_frames,
+                                     take_frame_every=take_frame_every,
+                                     integrator=integrator,
+                                     friction_coeff=friction_coeff,
+                                     step_size=step_size,
+                                     temperature_kelvin=system_temp,
+                                     replace_nonstandard_residues=replace_nonstandard_residues,
+                                     add_missing_atoms=add_missing_atoms,
+                                     add_missing_hydrogens=add_missing_hydrogens,
+                                     ignore_missing=ignore_missing_atoms)
         if simulation_result:
             self.experiments_loader.store_experiment(experiment_id, simulation_result)
             self.experiments_loader.save_experiment_metadata(experiment_id, experiment_name)
@@ -51,5 +70,6 @@ def inference(self, request: Request) -> dict:
         return {
             'id': experiment_id,
             'name': experiment_name,
-            'data': {'pdb': simulation_result}
+            'data': {'pdb': simulation_result},
+            'errors': errors
         }
diff --git a/src/server/frontend/src/storage.js b/src/server/frontend/src/storage.js
index 8da99e9e..7b1a7c4a 100644
--- a/src/server/frontend/src/storage.js
+++ b/src/server/frontend/src/storage.js
@@ -167,6 +167,7 @@ const store = createStore({
         },
         async conformations_inference({ commit }, { payload }) {
             const { form, experiment } = payload;
+            debugger;
             const formData = new FormData(form);
             formData.append('experimentId', experiment.id ?? '');
             formData.append('experimentName', experiment.name);
diff --git a/src/server/frontend/src/views/ConformationsFormView.vue b/src/server/frontend/src/views/ConformationsFormView.vue
index 88fc8100..e0f20b65 100644
--- a/src/server/frontend/src/views/ConformationsFormView.vue
+++ b/src/server/frontend/src/views/ConformationsFormView.vue
@@ -5,24 +5,110 @@ export default {
 </script>
 
 <template>
-    <form enctype="multipart/form-data" id="inferenceInputFormConformations"
-        v-on:submit.prevent="onFormSubmit">
-        <div class="row justify-content-center">
-            <div class="col-md-6">
-                <label for="proteinFileInput" class="col-form-label fs-4">.pdb file with molecule conformations</label>
-                <input type="file" multiple="multiple" accept="text/x-pdb" class="form-control" id="proteinFileInput"
-                    name="proteinFileInput">
+    <form enctype="multipart/form-data" id="inferenceInputFormConformations" class="row" v-on:submit.prevent="onFormSubmit">
+        <div class="justify-content-center col-md-5">
+            <label for="proteinFileInput" class="col-form-label fs-4">.pdb file with molecule conformations</label>
+            <input type="file" required multiple="multiple" accept="text/x-pdb" class="form-control" id="proteinFileInput"
+                name="proteinFileInput">
+        </div>
+        <div class="justify-content-center col-md-7 mt-2">
+            <h4>Simulation parameters</h4>
+            <div class="form-group row">
+                <label for="totalFramesInput" class="col-sm-4 col-form-label">Total frames</label>
+                <div class="col-sm-8">
+                    <input type="number" required min="0" step="1" class="form-control" id="totalFramesInput"
+                    name="totalFramesInput"
+                        aria-describedby="totalFramesInputHelp" placeholder="Total frames" value="20000">
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="takeFrameEveryInput" class="col-sm-4 col-form-label">Take frame every</label>
+                <div class="col-sm-8">
+                    <input type="number" required min="0" step="1" class="form-control" id="takeFrameEveryInput"
+                    name="takeFrameEveryInput"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Total frames" value="1000">
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="integratorSelect" class="col-sm-4 col-form-label">Integrator</label>
+                <div class="col-sm-8">
+                    <select class="form-select" required aria-label="Default select example" id="integratorSelect"
+                    name="integratorSelect">
+                        <option selected value="LangevinIntegator">Langevin integator</option>
+                        <option value="LangevinMiddleIntegrator">Langevin middle integator</option>
+                        <option value="NoseHooverIntegrator">Nose hoover integrator</option>
+                        <option value="BrownianIntegrator">Brownian integrator</option>
+                        <option value="VariableVerletIntegrator">Variable verlet integrator</option>
+                    </select>
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="frictionCoeffInput" class="col-sm-4 col-form-label">Friction coeff / 10<sup>-12</sup></label>
+                <div class="col-sm-8">
+                    <input type="number" min="0" required step="0.01" class="form-control" id="frictionCoeffInput"
+                    name="frictionCoeffInput"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Friction coeff" value="1">
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="stepSizeInput" class="col-sm-4 col-form-label">Step size / 10<sup>-12</sup></label>
+                <div class="col-sm-8">
+                    <input type="number" min="0" required step="0.001" class="form-control" id="stepSizeInput"
+                    name="stepSizeInput"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" value="0.002">
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="tempInput" class="col-sm-4 col-form-label">System temp in K</label>
+                <div class="col-sm-8">
+                    <input type="number" min="0" required step="0.001" class="form-control" id="tempInput"
+                    name="tempInput"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" value="273.15">
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="replaceNonstandardResiduesInput" class="col-sm-4 col-form-label">Replace nonstandard residues</label>
+                <div class="col-sm-8">
+                    <input type="checkbox" class="form-check-input" id="replaceNonstandardResiduesInput"
+                    name="replaceNonstandardResiduesInput"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" checked>
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="addMissingAtomsCheckbox" class="col-sm-4 col-form-label">Add missing atoms</label>
+                <div class="col-sm-8">
+                    <input type="checkbox" class="form-check-input" id="addMissingAtomsCheckbox"
+                    name="addMissingAtomsCheckbox"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" checked>
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="addMissingHydrogensCheckbox" class="col-sm-4 col-form-label">Add missing hydrogens</label>
+                <div class="col-sm-8">
+                    <input type="checkbox" class="form-check-input" id="addMissingHydrogensCheckbox"
+                    name="addMissingHydrogensCheckbox"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" checked>
+                </div>
+            </div>
+            <div class="mt-1 form-group row">
+                <label for="ignoreMissingAtomsCheckbox" class="col-sm-4 col-form-label">Ignore missing atoms</label>
+                <div class="col-sm-8">
+                    <input type="checkbox" class="form-check-input" id="ignoreMissingAtomsCheckbox"
+                    name="ignoreMissingAtomsCheckbox"
+                        aria-describedby="takeFrameEveryInputHelp" placeholder="Simulation step size" checked>
+                </div>
             </div>
         </div>
         <div class="row justify-content-center m-4">
             <div class="col-md-4">
-                <div class="btn-group mt-4" role="group"
-                    aria-label="Basic checkbox toggle button group">
+                <div class="btn-group mt-4" role="group" aria-label="Basic checkbox toggle button group">
                     <button type="submit" id="submitInference" class="btn btn-lg btn-primary">
                         Submit
                     </button>
                 </div>
             </div>
         </div>
+<hr/>
+
     </form>
 </template>
\ No newline at end of file
diff --git a/src/server/frontend/src/views/ConformationsLab.vue b/src/server/frontend/src/views/ConformationsLab.vue
index 32a6807b..19876bad 100644
--- a/src/server/frontend/src/views/ConformationsLab.vue
+++ b/src/server/frontend/src/views/ConformationsLab.vue
@@ -23,7 +23,7 @@ export default {
 <template>
     <ExperimentsView :state="experimentsState" :api="experimentsApi">
         <template v-slot:labTitle>
-            <h4>Conformations lab (pre-alpha)</h4>
+            <h2>Conformations lab (pre-alpha)</h2>
         </template>
         <template v-slot:labForm="labForm">
             <ConformationsFormView :onFormSubmit="labForm.onFormSubmit"/>
diff --git a/src/server/services/conformations/conformations_pipeline.py b/src/server/services/conformations/conformations_pipeline.py
index 60609d2b..df2e46ce 100644
--- a/src/server/services/conformations/conformations_pipeline.py
+++ b/src/server/services/conformations/conformations_pipeline.py
@@ -5,6 +5,7 @@
 from openmm.app import *
 from openmm import *
 from openmm.unit import *
+import re
 from werkzeug.datastructures import FileStorage
 
 from src.server.initializers.loggers import logger
@@ -17,209 +18,267 @@
 output_tmp_file = 'output.pdb'
 
 
-def remove_conformations_backups():
-    files = glob.glob('*.rtp*')
-    for f in files:
-        os.remove(f)
-    files = glob.glob('*.itp*')
-    for f in files:
-        os.remove(f)
-    files = glob.glob('*.gro*')
-    for f in files:
-        os.remove(f)
-
-
-def remove_pdbs():
-    files = glob.glob('*.pdb*')
-    for f in files:
-        os.remove(f)
-
-
-amber_files = {
-    'protein': [
-        'amber14-all.xml',
-        'amber14/protein.ff14SB.xml',
-        'amber14/protein.ff15ipq.xml',
-    ],
-    'dna': [
-        'amber14/DNA.OL15.xml',
-        'amber14/DNA.bsc1.xml',
-    ],
-    'rna': [
-        'amber14/RNA.OL3.xml',
-    ],
-    'lipid': [
-        'amber14/lipid17.xml',
-    ],
-    'carbohydrates': [
-        'amber14/GLYCAM_06j-1.xml',
-    ],
-    'water': [
-        'amber14/tip3p.xml',
-        'amber14/tip3pfb.xml',
-        'amber14/tip4pew.xml',
-        'amber14/tip4pfb.xml',
-        'amber14/spce.xml',
-        'amber14/opc.xml',
-        'amber14/opc3.xml'
-    ]
-}
-
-charmm = {
-    'protein': ['charmm36.xml'],
-    'water': [
-        'charmm36/water.xml',
-        'charmm36/spce.xml',
-        'charmm36/tip3p-pme-b.xml',
-        'charmm36/tip3p-pme-f.xml',
-        'charmm36/tip4pew.xml',
-        'charmm36/tip4p2005.xml',
-        'charmm36/tip5p.xml',
-        'charmm36/tip5pew.xml'
-    ]
-}
-
-gromacs_force_fields = {
-    'protein': ['amber03', 'amber94', 'amber96', 'amber99', 'amber99sb-ildn', 'amber99sb', 'amberGS', 'charmm27'],
-    'water': ['spc', 'spce', 'ip3p', 'tip4p', 'tip5p', 'tips3p']
-}
-
-
-def run_simulation_on_pdb(input_pdb, output_pdb, force_fields, report_every=1000, report_steps=10000):
-    try:
-        pdb = PDBFile(input_pdb)
-        forcefield = ForceField(*force_fields)
-        system = forcefield.createSystem(pdb.topology, nonbondedMethod=PME, nonbondedCutoff=1 * nanometer,
-                                         constraints=HBonds)
-        integrator = LangevinIntegrator(1 * kelvin, 1 / picosecond, 0.002 * picoseconds)
-        simulation = Simulation(pdb.topology, system, integrator)
-        simulation.context.setPositions(pdb.positions)
-        simulation.minimizeEnergy()
-        simulation.reporters.append(PDBReporter(output_pdb, report_every))
-        simulation.step(report_steps)
-        logger.info("Success!")
-        return True
-    except Exception as e:
-        logger.error(e)
-        return False
+def pipeline(pdb_content: FileStorage,
+             total_frames: int = 10000,
+             take_frame_every: int = 1000,
+             integrator: str = 'LangevinIntegator',
+             friction_coeff: float = 1,
+             step_size: float = 0.002,
+             temperature_kelvin: float = 273.15,
+             replace_nonstandard_residues: bool = True,
+             add_missing_atoms: bool = True,
+             add_missing_hydrogens: bool = True,
+             ignore_missing: bool = False):
+    '''
+    Run simulation
+    :param pdb_content: pdb content
+    :param total_frames: total frames to take
+    :param take_frame_every: take frame every nth
+    :param integrator: integrator, one of ['LangevinIntegator', 'LangevinMiddleIntegrator', 'NoseHooverIntegrator', 'BrownianIntegrator', 'VariableVerletIntegrator'].
+    See http://docs.openmm.org/7.1.0/api-python/library.html#integrators
+    :param friction_coeff ( picoseconds, default is 1 / picosecond ): see http://docs.openmm.org/7.1.0/api-python/generated/simtk.openmm.openmm.LangevinIntegrator.html
+    :param step_size: ( picoseconds, default is 0.002 / picoseconds ) see http://docs.openmm.org/7.1.0/api-python/generated/simtk.openmm.openmm.LangevinIntegrator.html
+    :param replace_nonstandard_residues: whether to replace nonstandard residues that cannot be found in standard dbs
+    :param add_missing_atoms: add missing atoms
+    :param add_missing_hydrogens: add missing hydrogens
+    :param ignore_missing: ignore missing. Dangerous. See https://manual.gromacs.org/documentation/current/onlinehelp/gmx-pdb2gmx.html -ignh option
+    :return:
+    '''
+
+    friction_coeff = friction_coeff / picosecond
+    step_size = step_size / picoseconds
+
+    def integrator_factory():
+        if integrator == 'LangevinIntegator':
+            return LangevinIntegrator
+        if integrator == 'LangevinMiddleIntegrator':
+            return LangevinMiddleIntegrator
+        if integrator == 'NoseHooverIntegrator':
+            return NoseHooverIntegrator
+        if integrator == 'BrownianIntegrator':
+            return BrownianIntegrator
+        if integrator == 'VariableVerletIntegrator':
+            return VariableVerletIntegrator
+
+    def remove_conformations_backups():
+        files = glob.glob('*.rtp*')
+        for f in files:
+            os.remove(f)
+        files = glob.glob('*.itp*')
+        for f in files:
+            os.remove(f)
+        files = glob.glob('*.gro*')
+        for f in files:
+            os.remove(f)
+
+    def remove_pdbs():
+        files = glob.glob('*.pdb*')
+        for f in files:
+            os.remove(f)
+
+    errors = []
+
+    amber_files = {
+        'protein': [
+            'amber14-all.xml',
+            'amber14/protein.ff14SB.xml',
+            'amber14/protein.ff15ipq.xml',
+        ],
+        'dna': [
+            'amber14/DNA.OL15.xml',
+            'amber14/DNA.bsc1.xml',
+        ],
+        'rna': [
+            'amber14/RNA.OL3.xml',
+        ],
+        'lipid': [
+            'amber14/lipid17.xml',
+        ],
+        'carbohydrates': [
+            'amber14/GLYCAM_06j-1.xml',
+        ],
+        'water': [
+            'amber14/tip3p.xml',
+            'amber14/tip3pfb.xml',
+            'amber14/tip4pew.xml',
+            'amber14/tip4pfb.xml',
+            'amber14/spce.xml',
+            'amber14/opc.xml',
+            'amber14/opc3.xml'
+        ]
+    }
+
+    charmm = {
+        'protein': ['charmm36.xml'],
+        'water': [
+            'charmm36/water.xml',
+            'charmm36/spce.xml',
+            'charmm36/tip3p-pme-b.xml',
+            'charmm36/tip3p-pme-f.xml',
+            'charmm36/tip4pew.xml',
+            'charmm36/tip4p2005.xml',
+            'charmm36/tip5p.xml',
+            'charmm36/tip5pew.xml'
+        ]
+    }
+
+    gromacs_force_fields = {
+        'protein': ['amber03', 'amber94', 'amber96', 'amber99', 'amber99sb-ildn', 'amber99sb', 'amberGS', 'charmm27'],
+        'water': ['spc', 'spce', 'ip3p', 'tip4p', 'tip5p', 'tips3p']
+    }
+
+    def extract_residues_from_errors():
+        errored_residues = []
+        for error in errors:
+            r = re.search('No template.*?\.', error)
+            if r:
+                residue = r.group(0).replace('No template found for residue', '').strip().strip('.')
+                errored_residues.append(residue)
+        return errored_residues
+
+    def run_simulation_on_pdb(input_pdb, output_pdb, force_fields):
+        try:
+            pdb = PDBFile(input_pdb)
+            forcefield = ForceField(*force_fields)
+            system = forcefield.createSystem(pdb.topology, nonbondedMethod=PME, nonbondedCutoff=1 * nanometer,
+                                             constraints=HBonds)
+            integrator_class = integrator_factory()
+            integrator = integrator_class(temperature_kelvin, friction_coeff, step_size)
+            simulation = Simulation(pdb.topology, system, integrator)
+            simulation.context.setPositions(pdb.positions)
+            simulation.minimizeEnergy()
+            simulation.reporters.append(PDBReporter(output_pdb, take_frame_every))
+            simulation.step(total_frames)
+            logger.info("Success!")
+            return True
+        except Exception as e:
+            logger.error(e)
+            errors.append(str(e))
+            return False
+
+    def run_simulation_on_gromacs(input_top, input_gro, output_pdb):
+        try:
+            gro = GromacsGroFile(input_gro)
+            top = GromacsTopFile(input_top, periodicBoxVectors=gro.getPeriodicBoxVectors(),
+                                 includeDir='/usr/local/gromacs/share/gromacs/top')
+            system = top.createSystem(nonbondedMethod=PME, nonbondedCutoff=1 * nanometer,
+                                      constraints=HBonds)
+            integrator_class = integrator_factory()
+            integrator = integrator_class(temperature_kelvin, friction_coeff, step_size)
+            simulation = Simulation(top.topology, system, integrator)
+            simulation.context.setPositions(gro.positions)
+            simulation.minimizeEnergy()
+            simulation.reporters.append(PDBReporter(output_pdb, take_frame_every))
+            simulation.step(total_frames)
+            return True
+        except Exception as e:
+            logger.error(e)
+            errors.append(str(e))
+            return False
 
+    def fix_pdb(input_pdb):
+        if replace_nonstandard_residues or add_missing_atoms or add_missing_hydrogens:
+            import pdbfixer
+            import openmm.app as mm_app
+            output_pdb = f'{input_pdb}-fixed.pdb'
+            if os.path.exists(output_pdb):
+                return output_pdb
+            fixer = pdbfixer.PDBFixer(input_pdb)
+            logger.info("Finding missing residues")
+            fixer.findMissingResidues()
+            logger.info("Finding nonstandard residues")
+            fixer.findNonstandardResidues()
+            logger.info('Finding missing atoms')
+            fixer.findMissingAtoms()
+            if replace_nonstandard_residues:
+                logger.info('Replacing nonstandard residues')
+                fixer.replaceNonstandardResidues()
+            if add_missing_atoms:
+                logger.info('Adding missing atoms')
+                fixer.addMissingAtoms()
+            if add_missing_hydrogens:
+                logger.info('Adding missing hydrogens')
+                fixer.addMissingHydrogens(7.0)
+            logger.info('Writing fixed file')
+            mm_app.PDBFile.writeFile(fixer.topology, fixer.positions, open(output_pdb, 'w'))
+            return output_pdb
+        return input_pdb
 
-def run_simulation_on_gromacs(input_top, input_gro, output_pdb, report_every=1000, report_steps=10000):
-    try:
-        gro = GromacsGroFile(input_gro)
-        top = GromacsTopFile(input_top, periodicBoxVectors=gro.getPeriodicBoxVectors(),
-                             includeDir='/usr/local/gromacs/share/gromacs/top')
-        system = top.createSystem(nonbondedMethod=PME, nonbondedCutoff=1 * nanometer,
-                                  constraints=HBonds)
-        integrator = LangevinMiddleIntegrator(1 * kelvin, 1 / picosecond, 0.002 * picoseconds)
-        simulation = Simulation(top.topology, system, integrator)
-        simulation.context.setPositions(gro.positions)
-        simulation.minimizeEnergy()
-        simulation.reporters.append(PDBReporter(output_pdb, report_every))
-        simulation.step(report_steps)
-        return True
-    except Exception as e:
-        logger.error(e)
+    def generate_gromacs_files(input_pdb, output_gro, topology_top, force_field, water):
+        res = subprocess.run(['/usr/local/gromacs/bin/gmx', 'pdb2gmx', '-f',
+                              input_pdb, '-o',
+                              output_gro, '-p',
+                              topology_top,
+                              '-ignh' if ignore_missing else '', '-ff', force_field.lower(), '-water', water.lower()],
+                             stdout=subprocess.PIPE, stderr=subprocess.PIPE, shell=False)
+        if os.path.exists(output_gro) and os.path.exists(topology_top):
+            logger.info(res.stdout.decode('utf-8')[:100])
+            return True
+        error = res.stderr.decode('utf-8')
+        errors.append(error)
+        logger.error(error[:100])
         return False
 
+    def permute_simulation(pdb_content: FileStorage):
+        remove_conformations_backups()
+        remove_pdbs()
+        pdb_content.save(pdb_tmp_file)
 
-def fix_pdb(input_pdb):
-    import pdbfixer
-    import openmm.app as mm_app
-
-    output_pdb = f'{input_pdb}-fixed.pdb'
-    if os.path.exists(output_pdb):
-        return output_pdb
-
-    fixer = pdbfixer.PDBFixer(input_pdb)
-    logger.info("Finding missing residues")
-    fixer.findMissingResidues()
-    logger.info("Finding nonstandard residues")
-    fixer.findNonstandardResidues()
-    logger.info('Replacing nonstandard residues')
-    fixer.replaceNonstandardResidues()
-    logger.info('Finding missing atoms')
-    fixer.findMissingAtoms()
-    logger.info('Adding missing atoms')
-    fixer.addMissingAtoms()
-    logger.info('Adding missing hydrogens')
-    fixer.addMissingHydrogens(7.0)
-    logger.info('Writing fixed file')
-    mm_app.PDBFile.writeFile(fixer.topology, fixer.positions, open(output_pdb, 'w'))
-    return output_pdb
-
-
-def generate_gromacs_files(input_pdb, output_gro, topology_top, force_field, water):
-    res = subprocess.run(['/usr/local/gromacs/bin/gmx', 'pdb2gmx', '-f',
-                          input_pdb, '-o',
-                          output_gro, '-p',
-                          topology_top,
-                          '-ignh', '-ff', force_field.lower(), '-water', water.lower()],
-                         stdout=subprocess.PIPE, stderr=subprocess.PIPE, shell=False)
-    if os.path.exists(output_gro) and os.path.exists(topology_top):
-        logger.info(res.stdout.decode('utf-8')[:100])
-        return True
-    logger.error(res.stderr.decode('utf-8')[:100])
-    return False
-
-
-def permute_simulation(pdb_content: FileStorage, report_every=1000, simulations_count=10000):
-    remove_conformations_backups()
-    remove_pdbs()
-    pdb_content.save(pdb_tmp_file)
-
-    def inner():
-        tries = [amber_files, charmm]
-
-        for input_pdb in [fix_pdb(pdb_tmp_file), pdb_tmp_file]:
-            for water in gromacs_force_fields['water']:
-                for force_field in gromacs_force_fields['protein']:
-                    logger.info(
-                        f'Trying to process your pdb by GROMACS using force field {force_field} and water {water}')
-                    gro = f'{input_pdb}.gro'
-                    top = f'{input_pdb}.top'
-                    res = generate_gromacs_files(input_pdb, f'{input_pdb}.gro', f'{input_pdb}.top', force_field,
-                                      water)
-                    if res and run_simulation_on_gromacs(top, gro, output_tmp_file, report_every, simulations_count):
-                        logger.info('Success')
-                        return
-                    remove_conformations_backups()
-
-            for t in tries:
-                for protein_force_fields in [pff for pff in t['protein']]:
-                    for water_force_fields in [wff for wff in t['water']]:
-                        logger.info(
-                            f'Trying to process your pdb by OPENMM using force field {protein_force_fields} and water {water_force_fields}')
+        def inner():
+            tries = [amber_files, charmm]
 
-                        sim_res = run_simulation_on_pdb(input_pdb, output_tmp_file,
-                                                        [protein_force_fields, water_force_fields])
-                        if sim_res:
+            for input_pdb in [fix_pdb(pdb_tmp_file), pdb_tmp_file]:
+                for water in gromacs_force_fields['water']:
+                    for force_field in gromacs_force_fields['protein']:
+                        logger.info(
+                            f'Trying to process your pdb by GROMACS using force field {force_field} and water {water}')
+                        gro = f'{input_pdb}.gro'
+                        top = f'{input_pdb}.top'
+                        res = generate_gromacs_files(input_pdb, f'{input_pdb}.gro', f'{input_pdb}.top', force_field,
+                                                     water)
+                        if res and run_simulation_on_gromacs(top, gro, output_tmp_file):
                             logger.info('Success')
                             return
                         remove_conformations_backups()
 
-                        other_force_fields_keys = [ff_key for ff_key in
-                                                   [key for key in t.keys() if key != 'water' and key != 'protein']]
+                for t in tries:
+                    for protein_force_fields in [pff for pff in t['protein']]:
+                        for water_force_fields in [wff for wff in t['water']]:
+                            logger.info(
+                                f'Trying to process your pdb by OPENMM using force field {protein_force_fields} and water {water_force_fields}')
 
-                        for key in other_force_fields_keys:
-                            force_fields = itertools.chain([protein_force_fields, water_force_fields], t[key])
-                            sim_res = run_simulation_on_pdb(input_pdb,
-                                                            output_tmp_file,
-                                                            force_fields, report_every, simulations_count)
+                            sim_res = run_simulation_on_pdb(input_pdb, output_tmp_file,
+                                                            [protein_force_fields, water_force_fields])
                             if sim_res:
                                 logger.info('Success')
                                 return
                             remove_conformations_backups()
-    try:
-        inner()
-
-        if os.path.exists(output_tmp_file):
-            with open(output_tmp_file, 'r') as f:
-                pdb_output = f.read()
-                return pdb_output
-        else:
-            logger.info('Unable to generate conformations for this .pdb file')
-            return
-    finally:
-        remove_conformations_backups()
-        remove_pdbs()
+
+                            other_force_fields_keys = [ff_key for ff_key in
+                                                       [key for key in t.keys() if key != 'water' and key != 'protein']]
+
+                            for key in other_force_fields_keys:
+                                force_fields = itertools.chain([protein_force_fields, water_force_fields], t[key])
+                                sim_res = run_simulation_on_pdb(input_pdb,
+                                                                output_tmp_file,
+                                                                force_fields)
+                                if sim_res:
+                                    logger.info('Success')
+                                    return
+                                remove_conformations_backups()
+
+        try:
+            inner()
+
+            if os.path.exists(output_tmp_file):
+                with open(output_tmp_file, 'r') as f:
+                    pdb_output = f.read()
+                    return (pdb_output, extract_residues_from_errors())
+            else:
+                logger.info('Unable to generate conformations for this .pdb file')
+                return (None, extract_residues_from_errors())
+        finally:
+            remove_conformations_backups()
+            remove_pdbs()
+
+    return permute_simulation(pdb_content)