{
 "cells": [
  {
   "cell_type": "markdown",
   "id": "fb270ec2-29da-4100-9485-39da5cce1663",
   "metadata": {},
   "source": [
    "# Reconstructing with BioCyc information and curated files\n",
    "\n",
    "In this tutorial we will reconstruct a _Bacillus subtilis_ ME-model from just the input files."
   ]
  },
  {
   "cell_type": "markdown",
   "id": "dbcc45ef-215d-4ee1-8383-bedd2efd084f",
   "metadata": {},
   "source": [
    "## Import libraries"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "d048f35f-6a3b-4642-86cd-49e4c4e4a187",
   "metadata": {
    "ExecuteTime": {
     "end_time": "2022-12-12T06:27:35.182100Z",
     "start_time": "2022-12-12T06:27:35.157355Z"
    }
   },
   "outputs": [],
   "source": [
    "from coralme.builder.main import MEBuilder\n",
    "import coralme"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "f40390ac-ebd6-4c7c-88dc-fb7d5b276383",
   "metadata": {},
   "source": [
    "## Path to configuration files"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "fe8269c7-24de-4f65-b01f-3412883f238e",
   "metadata": {},
   "source": [
    "For more information about these files see [Description of inputs](BasicInputs.ipynb). The configuration and layout used here is as shown in [this *B. subtilis* ME-model repository](https://github.com/jdtibochab/coralme-models/tree/main/published/bsubtilis)."
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "d62ee683-429e-481b-87ea-8758c47886bb",
   "metadata": {},
   "outputs": [],
   "source": [
    "organism = './bsubtilis/organism.json'\n",
    "inputs = './bsubtilis/input.json'"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "962f97bf-a03d-432f-916d-be11877033c4",
   "metadata": {},
   "source": [
    "## Create MEBuilder instance"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "f9988c4f-9bc2-4716-b8f9-46b02d533b90",
   "metadata": {},
   "source": [
    "For more information about this class see [Architecture of coralME](coralMEArchitecture.ipynb)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "f83fbefc-c392-496d-9e1e-7820d1b6d60b",
   "metadata": {
    "tags": []
   },
   "outputs": [],
   "source": [
    "builder = MEBuilder(*[organism, inputs])"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "32472ecb-9d39-477c-a611-3fb43d2e3254",
   "metadata": {},
   "source": [
    "## Generate files\n",
    "\n",
    "This corresponds to _Synchronyze_ and _Complement_ steps in [Architecture of coralME](coralMEArchitecture.ipynb)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "33e8a1a3-3206-4bc9-9407-3c31f5367d29",
   "metadata": {
    "ExecuteTime": {
     "end_time": "2022-12-12T06:30:28.060280Z",
     "start_time": "2022-12-12T06:30:01.706785Z"
    },
    "scrolled": true,
    "tags": []
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Initiating file processing...\n",
      "~ Processing files for bsubtilis...\n",
      "Set parameter Username\n",
      "Academic license - for non-commercial use only - expires 2025-09-03\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Checking M-model metabolites...                                            : 100.0%|██████████|   990/  990 [00:00<00:00]\n",
      "Checking M-model genes...                                                  : 100.0%|██████████|   844/  844 [00:00<00:00]\n",
      "Checking M-model reactions...                                              : 100.0%|██████████|  1250/ 1250 [00:00<00:00]\n",
      "Generating complexes dataframe from optional proteins file...              : 100.0%|██████████|  4554/ 4554 [00:00<00:00]\n",
      "Syncing optional genes file...                                             : 100.0%|██████████|  4541/ 4541 [00:00<00:00]\n",
      "Looking for duplicates within datasets...                                  : 100.0%|██████████|     5/    5 [00:00<00:00]\n",
      "Gathering ID occurrences across datasets...                                : 100.0%|██████████| 10647/10647 [00:00<00:00]\n",
      "Solving duplicates across datasets...                                      : 0.0%|          |     0/    0 [00:00<?]\n",
      "Pruning GenBank...                                                         : 100.0%|██████████|     1/    1 [00:01<00:00]\n",
      "Updating Genbank file with optional files...                               : 100.0%|██████████|  4541/ 4541 [00:00<00:00]\n",
      "Syncing optional files with genbank contigs...                             : 100.0%|██████████|     6/    6 [00:04<00:00]\n",
      "Modifying metabolites with manual curation...                              : 0.0%|          |     0/    0 [00:00<?]\n",
      "Modifying metabolic reactions with manual curation...                      : 100.0%|██████████|    36/   36 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "unknown metabolite '4crsol_c' created\n",
      "unknown metabolite 'dad__5_c' created\n",
      "unknown metabolite 'dhgly_c' created\n",
      "unknown metabolite '5drib_c' created\n",
      "unknown metabolite 'cu_e' created\n",
      "unknown metabolite 'cu_c' created\n",
      "unknown metabolite 'cbl1_e' created\n",
      "unknown metabolite 'cbl1_c' created\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Adding manual curation of complexes...                                     : 100.0%|██████████|   438/  438 [00:00<00:00]\n",
      "Getting sigma factors...                                                   : 100.0%|██████████|    38/   38 [00:00<00:00]\n",
      "Getting generics from Genbank contigs...                                   : 100.0%|██████████|     6/    6 [00:00<00:00]\n",
      "Getting TU-gene associations from optional TUs file...                     : 100.0%|██████████|  1647/ 1647 [00:00<00:00]\n",
      "Adding protein location...                                                 : 100.0%|██████████|  4683/ 4683 [00:00<00:00]\n",
      "Purging M-model genes...                                                   : 100.0%|██████████|   851/  851 [00:00<00:00]\n",
      "Getting enzyme-reaction associations...                                    : 100.0%|██████████|  1262/ 1262 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Reading bsubtilis done.\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Gathering M-model compartments...                                          : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Fixing compartments in M-model metabolites...                              : 100.0%|██████████|   998/  998 [00:00<00:00]\n",
      "Fixing missing names in M-model reactions...                               : 100.0%|██████████|  1262/ 1262 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "~ Processing files for iJL1678b...\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Checking M-model metabolites...                                            : 100.0%|██████████|  1660/ 1660 [00:00<00:00]\n",
      "Checking M-model genes...                                                  : 100.0%|██████████|  1271/ 1271 [00:00<00:00]\n",
      "Checking M-model reactions...                                              : 100.0%|██████████|  2377/ 2377 [00:00<00:00]\n",
      "Looking for duplicates within datasets...                                  : 100.0%|██████████|     5/    5 [00:00<00:00]\n",
      "Gathering ID occurrences across datasets...                                : 100.0%|██████████|  8517/ 8517 [00:00<00:00]\n",
      "Solving duplicates across datasets...                                      : 0.0%|          |     0/    0 [00:00<?]\n",
      "Getting sigma factors...                                                   : 100.0%|██████████|     7/    7 [00:00<00:00]\n",
      "Getting TU-gene associations from optional TUs file...                     : 100.0%|██████████|  1647/ 1647 [00:00<00:00]\n",
      "Adding protein location...                                                 : 100.0%|██████████|  1304/ 1304 [00:00<00:00]\n",
      "Purging M-model genes...                                                   : 100.0%|██████████|  1271/ 1271 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Reading iJL1678b done.\n",
      "~ Running BLAST with 1 threads...\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Converting Genbank contigs to FASTA for BLAST...                           : 100.0%|██████████|     6/    6 [00:00<00:00]\n",
      "Converting Genbank contigs to FASTA for BLAST...                           : 100.0%|██████████|     1/    1 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "BLAST done.\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Updating translocation machinery from homology...                          : 100.0%|██████████|     9/    9 [00:00<00:00]\n",
      "Updating protein location from homology...                                 : 100.0%|██████████|   514/  514 [00:00<00:00]\n",
      "Updating translocation multipliers from homology...                        : 100.0%|██████████|     3/    3 [00:00<00:00]\n",
      "Updating lipoprotein precursors from homology...                           : 100.0%|██████████|    14/   14 [00:00<00:00]\n",
      "Updating cleaved-methionine proteins from homology...                      : 100.0%|██████████|   343/  343 [00:00<00:00]\n",
      "Mapping M-metabolites to E-metabolites...                                  : 100.0%|██████████|   147/  147 [00:00<00:00]\n",
      "Updating generics from homology...                                         : 100.0%|██████████|    10/   10 [00:00<00:00]\n",
      "Updating folding from homology...                                          : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Updating ribosome subreaction machinery from homology...                   : 100.0%|██████████|     3/    3 [00:00<00:00]\n",
      "Updating tRNA synthetases from homology...                                 : 100.0%|██████████|    20/   20 [00:00<00:00]\n",
      "Updating peptide release factors from homology...                          : 100.0%|██████████|     3/    3 [00:00<00:00]\n",
      "Updating transcription subreactions machinery from homology...             : 100.0%|██████████|     4/    4 [00:00<00:00]\n",
      "Updating translation initiation subreactions from homology...              : 100.0%|██████████|     4/    4 [00:00<00:00]\n",
      "Updating translation elongation subreactions from homology...              : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Updating translation termination subreactions from homology...             : 100.0%|██████████|     9/    9 [00:00<00:00]\n",
      "Updating special tRNA subreactions from homology...                        : 100.0%|██████████|     1/    1 [00:00<00:00]\n",
      "Updating RNA degradosome composition from homology...                      : 100.0%|██████████|     1/    1 [00:00<00:00]\n",
      "Updating excision machinery from homology...                               : 100.0%|██████████|     3/    3 [00:00<00:00]\n",
      "Updating tRNA subreactions from homology...                                : 100.0%|██████████|     6/    6 [00:00<00:00]\n",
      "Updating lipid modification machinery from homology...                     : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Fixing M-model metabolites with homology...                                : 100.0%|██████████|   998/  998 [00:00<00:00]\n",
      "Updating enzyme reaction association...                                    : 100.0%|██████████|   922/  922 [00:00<00:00]\n",
      "Getting tRNA to codon dictionary from NC_000964.3                          : 100.0%|██████████|  4537/ 4537 [00:03<00:00]\n",
      "Getting tRNA to codon dictionary from BSU_misc_RNA_38                      : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Getting tRNA to codon dictionary from G8J2-183                             : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Getting tRNA to codon dictionary from G8J2-180                             : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Getting tRNA to codon dictionary from G8J2-181                             : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Getting tRNA to codon dictionary from G8J2-182                             : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Checking defined translocation pathways...                                 : 100.0%|██████████|     9/    9 [00:00<00:00]\n",
      "Getting reaction Keffs...                                                  : 100.0%|██████████|   922/  922 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Writting the Organism-Specific Matrix...\n",
      "Organism-Specific Matrix saved to ./bsubtilis/building_data/automated-org-with-refs.xlsx file.\n",
      "File processing done.\n"
     ]
    }
   ],
   "source": [
    "builder.generate_files(overwrite=True)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "0e9f5993-cbad-44e9-a1ce-51c43e69f565",
   "metadata": {},
   "source": [
    "## Build ME-model\n",
    "\n",
    "This corresponds to _Build_ in [Architecture of coralME](coralMEArchitecture.ipynb)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "df64d444-7726-4ab3-b597-74990636c428",
   "metadata": {
    "ExecuteTime": {
     "end_time": "2022-12-12T06:28:36.607889Z",
     "start_time": "2022-12-12T06:27:59.542579Z"
    },
    "scrolled": true,
    "tags": []
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Initiating ME-model reconstruction...\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Adding biomass constraint(s) into the ME-model...                          : 100.0%|██████████|    11/   11 [00:00<00:00]"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Read LP format model from file /tmp/tmp7trh8uhg.lp\n",
      "Reading time = 0.00 seconds\n",
      ": 997 rows, 2524 columns, 10562 nonzeros\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Read LP format model from file /tmp/tmp575tct7k.lp\n",
      "Reading time = 0.00 seconds\n",
      ": 997 rows, 2520 columns, 10544 nonzeros\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Adding Metabolites from M-model into the ME-model...                       : 100.0%|██████████|  1087/ 1087 [00:00<00:00]\n",
      "Adding Reactions from M-model into the ME-model...                         : 100.0%|██████████|  1277/ 1277 [00:00<00:00]\n",
      "Adding Transcriptional Units into the ME-model from user input...          : 100.0%|██████████|  1515/ 1515 [00:09<00:00]\n",
      "Adding features from contig NC_000964.3 into the ME-model...               : 100.0%|██████████|  4537/ 4537 [00:09<00:00]\n",
      "Adding features from contig BSU_misc_RNA_38 into the ME-model...           : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Adding features from contig G8J2-183 into the ME-model...                  : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Adding features from contig G8J2-180 into the ME-model...                  : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Adding features from contig G8J2-181 into the ME-model...                  : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Adding features from contig G8J2-182 into the ME-model...                  : 100.0%|██████████|     2/    2 [00:00<00:00]\n",
      "Updating all TranslationReaction and TranscriptionReaction...              : 100.0%|██████████|  8389/ 8389 [00:21<00:00]\n",
      "Removing SubReactions from ComplexData...                                  : 100.0%|██████████|  5007/ 5007 [00:00<00:00]\n",
      "Adding ComplexFormation into the ME-model...                               : 100.0%|██████████|  5007/ 5007 [00:00<00:00]\n",
      "Adding Generic(s) into the ME-model...                                     : 100.0%|██████████|    10/   10 [00:00<00:00]\n",
      "Processing StoichiometricData in ME-model...                               : 100.0%|██████████|  1045/ 1045 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "ME-model was saved in the ./bsubtilis/ directory as MEModel-step1-bsubtilis.pkl\n"
     ]
    },
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "Adding tRNA synthetase(s) information into the ME-model...                 : 100.0%|██████████|   306/  306 [00:00<00:00]\n",
      "Adding tRNA modification SubReactions...                                   : 100.0%|██████████|    19/   19 [00:00<00:00]\n",
      "Associating tRNA modification enzyme(s) to tRNA(s)...                      : 100.0%|██████████|    33/   33 [00:00<00:00]\n",
      "Adding SubReactions into TranslationReactions...                           : 100.0%|██████████|  4328/ 4328 [00:01<00:00]\n",
      "Adding RNA Polymerase(s) into the ME-model...                              : 100.0%|██████████|    39/   39 [00:00<00:00]\n",
      "Associating a RNA Polymerase to each Transcriptional Unit...               : 100.0%|██████████|  1515/ 1515 [00:00<00:00]\n",
      "Processing ComplexData in ME-model...                                      : 100.0%|██████████|   322/  322 [00:00<00:00]\n",
      "Adding ComplexFormation into the ME-model...                               : 100.0%|██████████|  5054/ 5054 [00:00<00:00]\n",
      "Adding SubReactions into TranslationReactions...                           : 100.0%|██████████|  4328/ 4328 [00:08<00:00]\n",
      "Adding Transcription SubReactions...                                       : 100.0%|██████████|  3513/ 3513 [00:00<00:00]\n",
      "Processing StoichiometricData in SubReactionData...                        : 100.0%|██████████|  1650/ 1650 [00:00<00:00]\n",
      "Adding reaction subsystems from M-model into the ME-model...               : 100.0%|██████████|  1277/ 1277 [00:00<00:00]\n",
      "Processing StoichiometricData in ME-model...                               : 100.0%|██████████|  1045/ 1045 [00:00<00:00]\n",
      "Updating ME-model Reactions...                                             : 100.0%|██████████| 17480/17480 [01:25<00:00]\n",
      "Updating all FormationReactions...                                         : 100.0%|██████████|  5054/ 5054 [00:00<00:00]\n",
      "Recalculation of the elemental contribution in SubReactions...             : 100.0%|██████████|   277/  277 [00:00<00:00]\n",
      "Updating all FormationReactions...                                         : 100.0%|██████████|  5054/ 5054 [00:00<00:00]\n",
      "Updating FormationReactions involving a lipoyl prosthetic group...         : 100.0%|██████████|     3/    3 [00:00<00:00]\n",
      "Updating FormationReactions involving a glycyl radical...                  : 0.0%|          |     0/    0 [00:00<?]\n",
      "Estimating effective turnover rates for reactions using the SASA method... : 100.0%|██████████|  2882/ 2882 [00:00<00:00]\n",
      "Mapping effective turnover rates from user input...                        : 0.0%|          |     0/    0 [00:00<?]\n",
      "Setting the effective turnover rates using user input...                   : 100.0%|██████████|  2632/ 2632 [00:00<00:00]\n",
      "Pruning unnecessary ComplexData reactions...                               : 100.0%|██████████|  5054/ 5054 [00:06<00:00]\n",
      "Pruning unnecessary FoldedProtein reactions...                             : 0.0%|          |     0/    0 [00:00<?]\n",
      "Pruning unnecessary ProcessedProtein reactions...                          : 100.0%|██████████|  5647/ 5647 [00:01<00:00]\n",
      "Pruning unnecessary TranslatedGene reactions...                            : 100.0%|██████████|  4640/ 4640 [00:09<00:00]\n",
      "Pruning unnecessary TranscribedGene reactions...                           : 100.0%|██████████|  4540/ 4540 [00:05<00:00]\n",
      "Pruning unnecessary Transcriptional Units...                               : 100.0%|██████████|  3513/ 3513 [00:03<00:00]\n",
      "Pruning unnecessary ComplexData reactions...                               : 100.0%|██████████|   988/  988 [00:00<00:00]\n",
      "Pruning unnecessary FoldedProtein reactions...                             : 0.0%|          |     0/    0 [00:00<?]\n",
      "Pruning unnecessary ProcessedProtein reactions...                          : 100.0%|██████████|  1354/ 1354 [00:00<00:00]\n",
      "Pruning unnecessary TranslatedGene reactions...                            : 100.0%|██████████|  1354/ 1354 [00:00<00:00]\n",
      "Pruning unnecessary TranscribedGene reactions...                           : 100.0%|██████████|  1159/ 1159 [00:02<00:00]\n",
      "Pruning unnecessary Transcriptional Units...                               : 100.0%|██████████|   792/  792 [00:01<00:00]\n",
      "Pruning unnecessary ComplexData reactions...                               : 100.0%|██████████|   965/  965 [00:00<00:00]\n",
      "Pruning unnecessary FoldedProtein reactions...                             : 0.0%|          |     0/    0 [00:00<?]\n",
      "Pruning unnecessary ProcessedProtein reactions...                          : 100.0%|██████████|  1352/ 1352 [00:00<00:00]\n",
      "Pruning unnecessary TranslatedGene reactions...                            : 100.0%|██████████|  1352/ 1352 [00:00<00:00]\n",
      "Pruning unnecessary TranscribedGene reactions...                           : 100.0%|██████████|  1157/ 1157 [00:01<00:00]\n",
      "Pruning unnecessary Transcriptional Units...                               : 100.0%|██████████|   790/  790 [00:01<00:00]\n",
      "Pruning unnecessary ComplexData reactions...                               : 100.0%|██████████|   964/  964 [00:00<00:00]\n",
      "Pruning unnecessary FoldedProtein reactions...                             : 0.0%|          |     0/    0 [00:00<?]\n",
      "Pruning unnecessary ProcessedProtein reactions...                          : 100.0%|██████████|  1351/ 1351 [00:00<00:00]\n",
      "Pruning unnecessary TranslatedGene reactions...                            : 100.0%|██████████|  1351/ 1351 [00:00<00:00]\n",
      "Pruning unnecessary TranscribedGene reactions...                           : 100.0%|██████████|  1156/ 1156 [00:02<00:00]\n",
      "Pruning unnecessary Transcriptional Units...                               : 100.0%|██████████|   789/  789 [00:00<00:00]\n"
     ]
    },
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "ME-model was saved in the ./bsubtilis/ directory as MEModel-step2-bsubtilis.pkl\n",
      "ME-model reconstruction is done.\n",
      "Number of metabolites in the ME-model is 4630 (+364.39%, from 997)\n",
      "Number of reactions in the ME-model is 7758 (+514.74%, from 1262)\n",
      "Number of genes in the ME-model is 1154 (+36.73%, from 844)\n",
      "Number of missing genes from reconstruction with homology, but no function is 104. Check the curation notes for more details.\n"
     ]
    }
   ],
   "source": [
    "builder.build_me_model(overwrite=False)"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "eb86277a-16e5-490b-bcb2-99e0536e49da",
   "metadata": {},
   "source": [
    "## Troubleshoot ME-model\n",
    "\n",
    "This corresponds to _Find gaps_ in [Architecture of coralME](coralMEArchitecture.ipynb)"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "49a10838-9065-402e-a364-0898f5a4d2ad",
   "metadata": {
    "tags": []
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "The MINOS and quad MINOS solvers are a courtesy of Prof Michael A. Saunders. Please cite Ma, D., Yang, L., Fleming, R. et al. Reliable and efficient solution of genome-scale models of Metabolism and macromolecular Expression. Sci Rep 7, 40863 (2017). https://doi.org/10.1038/srep40863\n",
      "\n",
      "~ Troubleshooting started...\n",
      "  Checking if the ME-model can simulate growth without gapfilling reactions...\n",
      "  Original ME-model is feasible with a tested growth rate of 0.001000 1/h\n",
      "~ Final step. Fully optimizing with precision 1e-6 and save solution into the ME-model...\n",
      "  Gapfilled ME-model is feasible with growth rate 0.101279 (M-model: 0.117966).\n",
      "ME-model was saved in the ./bsubtilis/ directory as MEModel-step3-bsubtilis-TS.pkl\n"
     ]
    }
   ],
   "source": [
    "builder.troubleshoot(growth_key_and_value = { builder.me_model.mu : 0.001 },solver=\"qminos\")"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "cad22d76-a979-4ac8-a7ea-f1885d041c6a",
   "metadata": {},
   "source": [
    "<div class=\"alert alert-info\">\n",
    "**Note**: We set 0.001 as a standard value for feasibility checking, but feel free to modify it! Sometimes too high a value could put a significant strain on the model and give too many gaps to start with. Too low a value might not show you all the gaps needed.\n",
    "</div>"
   ]
  },
  {
   "cell_type": "markdown",
   "id": "88421b3b-8b8f-4956-8888-98876d6e1df8",
   "metadata": {},
   "source": [
    "## Save as a JSON"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "4927e5f7-97c0-4504-86cc-d1436d6482fa",
   "metadata": {},
   "outputs": [
    {
     "name": "stderr",
     "output_type": "stream",
     "text": [
      "2024-11-26 17:43:32,509 The metabolite 'pg160_p' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,510 The metabolite '2agpg160_p' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,510 The metabolite 'pe160_p' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,510 The metabolite '2agpe160_p' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,909 Metabolite '4fe4s_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,910 Metabolite '4fe4s_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,910 Metabolite '2fe2s_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,910 Metabolite '2fe2s_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,910 Metabolite 'hemed_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,911 Metabolite 'hemed_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,911 Metabolite 'fmnh2_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,911 Metabolite 'fmnh2_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,912 Metabolite 'tl_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,912 Metabolite 'tl_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,912 Metabolite 'cs_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,912 Metabolite 'cs_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,913 The metabolite 'adocbl_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,913 The metabolite 'adocbl_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,913 The metabolite 'coo_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,913 The metabolite 'coo_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,913 The metabolite 'cosh_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,914 The metabolite 'cosh_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,914 The metabolite 'lipo_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,914 The metabolite 'lipo_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,914 Metabolite 'lipoyl_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,914 Metabolite 'lipoyl_c' does not have a formula. If it is a 'Complex', its formula will be determined from amino acid composition and prosthetic groups stoichiometry. Otherwise, please add it to the M-model.\n",
      "2024-11-26 17:43:32,915 The metabolite 'li_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,915 The metabolite 'li_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,915 The metabolite 'cl_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,915 The metabolite 'cl_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,915 The metabolite 'bmocogdp_c' must exist in the ME-model to calculate the element contribution.\n",
      "2024-11-26 17:43:32,915 The metabolite 'bmocogdp_c' must exist in the ME-model to calculate the element contribution.\n"
     ]
    }
   ],
   "source": [
    "coralme.io.json.save_json_me_model(builder.me_model,\"./bsubtilis/MEModel-step3-bsubtilis-TS.json\")"
   ]
  }
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