cov318_no_thresholds.ipynb

{
 "cells": [
  {
   "cell_type": "code",
   "execution_count": 1,
   "id": "6a983329",
   "metadata": {},
   "outputs": [],
   "source": [
    "from cobra.io import read_sbml_model\n",
    "from mewpy.simulation import get_simulator\n",
    "import pandas as pd\n",
    "import matplotlib.pyplot as plt\n",
    "import cobra\n",
    "import numpy as np\n",
    "import csv\n",
    "from pandas import DataFrame\n",
    "import statistics\n",
    "import seaborn as sns\n",
    "import plotly\n",
    "import plotly.express as px\n",
    "import plotly.graph_objs as go\n",
    "from mewpy.simulation import set_default_solver\n",
    "set_default_solver('gurobi')"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 2,
   "id": "0fd9821b",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "no stored variable or alias #set\n",
      "no stored variable or alias per\n",
      "no stored variable or alias cell\n",
      "no stored variable or alias line\n",
      "row: 57\n"
     ]
    }
   ],
   "source": [
    "%store -r t_2020_4\n",
    "expression = t_2020_4.transpose()\n",
    "%store -r media_only_essential_reactions\n",
    "%store -r media_only_essential_genes\n",
    "%store -r DMEM_2mM_glutamine #set per cell line\n",
    "media = DMEM_2mM_glutamine\n",
    "indexes = list(range(0, 64))\n",
    "for n in range(len((t_2020_4.index).to_list())):\n",
    "    if 'COV318' == ((t_2020_4.index).to_list())[n]: #set per cell line\n",
    "        t = n\n",
    "row_number_transcriptomics = t\n",
    "print('row:',t)\n"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 3,
   "id": "1ed7a9e0",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "Index(['COV434', '59M', 'NZOV9', 'OAW42', 'COV644', 'TO14', 'COV413A', 'OAW28',\n",
       "       'JHOC5', 'JHOS4', 'FUOV1', 'OVMANA', 'TYKNU', 'PEO1', 'CAOV3', 'RMGI',\n",
       "       'BIN67', 'OELE', 'OVK18', 'JHOS2', 'ES2', 'JHOM1', 'EFO27', 'HSKTC',\n",
       "       'OV7', 'OVSAHO', 'NIHOVCAR3', 'OCIC4P', 'OVISE', 'KURAMOCHI', 'COV362',\n",
       "       'OVCAR8', 'PA1', 'OC316', 'OCIC5X', 'OV17R', 'SKOV3', 'EFO21',\n",
       "       'TOV112D', 'OC314', 'SNU119', 'IGROV1', 'A2780', 'SNU840', 'CAOV4',\n",
       "       'JHOM2B', 'OVCAR4', 'SCCOHT1', 'PEA1', 'OCIP5X', 'OV56', 'ONCODG1',\n",
       "       'SNU8', 'OVKATE', 'OVTOKO', 'OV90', 'MCAS', 'COV318', 'OVCAR5', 'RMUGS',\n",
       "       'HEYA8', 'PEO4', 'COV504', 'TOV21G'],\n",
       "      dtype='object', name='cell_line')"
      ]
     },
     "execution_count": 3,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "t_2020_4.index "
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 4,
   "id": "13787455",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "Set parameter Username\n",
      "Academic license - for non-commercial use only - expires 2024-03-24\n"
     ]
    },
    {
     "data": {
      "text/html": [
       "<div>\n",
       "<style scoped>\n",
       "    .dataframe tbody tr th:only-of-type {\n",
       "        vertical-align: middle;\n",
       "    }\n",
       "\n",
       "    .dataframe tbody tr th {\n",
       "        vertical-align: top;\n",
       "    }\n",
       "\n",
       "    .dataframe thead th {\n",
       "        text-align: right;\n",
       "    }\n",
       "</style>\n",
       "<table border=\"1\" class=\"dataframe\">\n",
       "  <thead>\n",
       "    <tr style=\"text-align: right;\">\n",
       "      <th></th>\n",
       "      <th>Flux rate</th>\n",
       "    </tr>\n",
       "    <tr>\n",
       "      <th>Reaction ID</th>\n",
       "      <th></th>\n",
       "    </tr>\n",
       "  </thead>\n",
       "  <tbody>\n",
       "    <tr>\n",
       "      <th>biomass_human</th>\n",
       "      <td>0.213772</td>\n",
       "    </tr>\n",
       "  </tbody>\n",
       "</table>\n",
       "</div>"
      ],
      "text/plain": [
       "               Flux rate\n",
       "Reaction ID             \n",
       "biomass_human   0.213772"
      ]
     },
     "execution_count": 4,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "model = read_sbml_model('Human-GEM-annotated.xml')\n",
    "media_only_simulation = get_simulator(model, envcond = media)\n",
    "media_only_result = media_only_simulation.simulate()\n",
    "media_only_result.find(['biomass_human'])"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 5,
   "id": "a31e5710",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "AND rules:  653\n",
      "ANDOR rules:  129\n",
      "OR rules:  3972\n",
      "ONE GENE rules:  3282\n",
      "NO GENE rules:  5060\n",
      "Proportion of model not annotated:  38.63775198533904 %\n",
      "Proportion of model which IS annotated:  61.36224801466096 %\n",
      "Total Reactions =  13096\n",
      "13096\n",
      "number of reversible, one gene reactions = 1074\n",
      "number of forward, one gene reactions = 2208\n"
     ]
    }
   ],
   "source": [
    "expression = expression.transpose()\n",
    "t = expression\n",
    "gene_exp = t.iloc[row_number_transcriptomics,:]\n",
    "\n",
    "g_list = []\n",
    "for k in gene_exp.keys():\n",
    "    g_list.append(k)\n",
    "    \n",
    "g_list = []\n",
    "for k in gene_exp.keys():\n",
    "    g_list.append(k)\n",
    "\n",
    "g_ensembl = []\n",
    "for n in range(len(g_list)):\n",
    "    if 'ENS' not in (g_list[n].split())[0]:\n",
    "        g_ensembl.append((g_list[n].split())[1])\n",
    "    if 'ENS' in (g_list[n].split())[0]:\n",
    "        g_ensembl.append((g_list[n].split())[0])\n",
    "        \n",
    "punc = '''!()-[]{};:'\"\\,<>./?@#$%^&*_~'''\n",
    "g_ensembl_2 = []\n",
    "for n in range(len(g_ensembl)):\n",
    "    for x in g_ensembl[n]:\n",
    "        if x in punc:\n",
    "            g_ensembl[n] = g_ensembl[n].replace(x, \"\")\n",
    "    g_ensembl_2.append(g_ensembl[n])\n",
    "g_ensembl_2\n",
    "\n",
    "vs = []\n",
    "for v in gene_exp:\n",
    "    vs.append(v)\n",
    "    \n",
    "gene_exp_dict = {}\n",
    "for n in range(len(g_ensembl_2)):\n",
    "    gene_exp_dict[g_ensembl_2[n]] = vs[n]\n",
    "    \n",
    "ANDs = []\n",
    "ORs = []\n",
    "ANDORs = []\n",
    "one_gene = []\n",
    "no_gene = []\n",
    "\n",
    "for r in model.reactions:\n",
    "    if 'and' in r.gene_reaction_rule and 'or' not in r.gene_reaction_rule:\n",
    "        ANDs.append(r.id)\n",
    "    if 'and' in r.gene_reaction_rule and 'or' in r.gene_reaction_rule:\n",
    "        ANDORs.append(r.id)\n",
    "    if 'or' in r.gene_reaction_rule and 'and' not in r.gene_reaction_rule:\n",
    "        ORs.append(r.id)\n",
    "    if len(r.gene_reaction_rule) == 0:\n",
    "        no_gene.append(r.id)\n",
    "    if len(r.gene_reaction_rule) != 0:\n",
    "        if 'or' in r.gene_reaction_rule:\n",
    "            continue\n",
    "        elif 'and' in r.gene_reaction_rule:\n",
    "            continue\n",
    "        else:\n",
    "            one_gene.append(r.id)\n",
    "\n",
    "print('AND rules: ', len(ANDs))\n",
    "print('ANDOR rules: ', len(ANDORs))\n",
    "print('OR rules: ', len(ORs))\n",
    "print('ONE GENE rules: ', len(one_gene))\n",
    "print('NO GENE rules: ', len(no_gene))\n",
    "print('Proportion of model not annotated: ', len(no_gene)/len(model.reactions)*100, '%')\n",
    "print('Proportion of model which IS annotated: ', 100-(len(no_gene)/len(model.reactions)*100), '%')\n",
    "print('Total Reactions = ', len(model.reactions))\n",
    "print(len(ORs)+len(ANDs)+len(ANDORs)+len(one_gene)+len(no_gene))\n",
    "\n",
    "one_gene_forward = []\n",
    "one_gene_reversible = []\n",
    "for r in one_gene:\n",
    "    if model.reactions.get_by_id(r).reversibility == True:\n",
    "        one_gene_reversible.append(r)\n",
    "    else:\n",
    "        one_gene_forward.append(r)\n",
    "print('number of reversible, one gene reactions =', len(one_gene_reversible))\n",
    "print('number of forward, one gene reactions =', len(one_gene_forward))"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 6,
   "id": "2f131bc0",
   "metadata": {},
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "growth with media constraints only:  0.21377181121424527 g/gDW/hour = 4.6778852380952385 hours\n"
     ]
    }
   ],
   "source": [
    "media_only_simulation = get_simulator(model, envcond = media)\n",
    "media_only_result = media_only_simulation.simulate()\n",
    "print('growth with media constraints only: ', media_only_result.find(['biomass_human']).iloc[0,0],\n",
    "      'g/gDW/hour','=',(1/media_only_result.find(['biomass_human']).iloc[0,0]),'hours')"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": 7,
   "id": "d64bc288",
   "metadata": {},
   "outputs": [
    {
     "data": {
      "text/plain": [
       "0.21377181121424527"
      ]
     },
     "execution_count": 7,
     "metadata": {},
     "output_type": "execute_result"
    }
   ],
   "source": [
    "media_only_result.find(['biomass_human']).iloc[0,0]"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "617376cb",
   "metadata": {
    "scrolled": true
   },
   "outputs": [
    {
     "name": "stdout",
     "output_type": "stream",
     "text": [
      "HMR_3907 : (0, 6.4932950705035815) 0.21377181121424527\n",
      "HMR_4097 : (0, 4.571676809970931) 0.21377181121424527\n",
      "HMR_4108 : (0, 4.571676809970931) 0.21377181121424527\n",
      "HMR_4133 : (0, 4.571676809970931) 0.21377181121424527\n",
      "HMR_4360 : (0, 2.448900951145128) 0.21377181121424527\n",
      "HMR_4372 : (0, 4.228049047884462) 0.21377181121424527\n",
      "HMR_7747 : (0, 4.450881315273369) 0.21377181121424527\n",
      "HMR_8360 : (0, 2.2600256559614555) 0.21377181121424527\n",
      "HMR_8757 : (0, 0.8073549220576041) 0.21377181121424527\n",
      "HMR_5397 : (0, 4.07724299893246) 0.21377181121424527\n",
      "HMR_5399 : (0, 2.62993940943954) 0.21377181121424527\n",
      "HMR_5400 : (0, 2.62993940943954) 0.21377181121424527\n",
      "HMR_8592 : (0, 4.425593577653059) 0.21377181121424527\n",
      "HMR_8589 : (0, 4.425593577653059) 0.21377181121424527\n",
      "HMR_8583 : (0, 0.1890338243900171) 0.21377181121424527\n",
      "HMR_8584 : (0, 0.0) 0.21377181121424527\n",
      "HMR_8585 : (0, 2.056583528366368) 0.21377181121424527\n",
      "HMR_3944 : (0, 5.518849828707692) 0.21377181121424527\n",
      "HMR_4132 : (0, 3.84197311892718) 0.21377181121424527\n",
      "HMR_8761 : (0, 0.8639384504239714) 0.21377181121424527\n",
      "HMR_8764 : (0, 0.0) 0.21377181121424527\n",
      "HMR_8767 : (0, 3.84197311892718) 0.21377181121424527\n",
      "HMR_4310 : (0, 0.8639384504239714) 0.21377181121424527\n",
      "HMR_4399 : (0, 4.698218478224414) 0.21377181121424527\n",
      "HMR_4400 : (0, 4.436961337833602) 0.21377181121424527\n",
      "HMR_8768 : (0, 4.436961337833602) 0.21377181121424527\n",
      "HMR_4590 : (0, 5.24412594328373) 0.21377181121424527\n",
      "HMR_4593 : (0, 3.682573297347578) 0.21377181121424527\n",
      "HMR_4594 : (0, 0.4222330006830478) 0.21377181121424527\n",
      "HMR_8726 : (0, 2.4329594072761065) 0.21377181121424527\n",
      "HMR_8727 : (0, 3.896271848807375) 0.21377181121424527\n",
      "HMR_8729 : (0, 5.241458871274651) 0.21377181121424527\n",
      "HMR_4093 : (0, 0.0) 0.21377181121424527\n",
      "HMR_4095 : (0, 0.0) 0.21377181121424527\n",
      "HMR_4101 : (0, 0.0565835283663675) 0.21377181121424527\n",
      "HMR_4103 : (0, 3.400537929583729) 0.21377181121424527\n",
      "HMR_4143 : (0, 2.817623257511431) 0.21377181121424527\n",
      "HMR_8498 : (0, 0.8073549220576041) 0.21377181121424527\n",
      "HMR_8499 : (0, 0.8073549220576041) 0.21377181121424527\n",
      "HMR_8501 : (0, 5.41886457739032) 0.21377181121424527\n",
      "HMR_8516 : (0, 2.8011586560936985) 0.21377181121424527\n",
      "HMR_4105 : (0, 0.8875252707415875) 0.21377181121424527\n",
      "HMR_4106 : (0, 0.8875252707415875) 0.21377181121424527\n",
      "HMR_4107 : (0, 0.8875252707415875) 0.21377181121424527\n",
      "HMR_4282 : (0, 2.538538163629804) 0.21377181121424527\n",
      "HMR_4741 : (0, 4.05484847699562) 0.21377181121424527\n",
      "HMR_0718 : (0, 3.23112515787905) 0.21377181121424527\n",
      "HMR_0719 : (0, 6.896635141302909) 0.21377181121424527\n",
      "HMR_1436 : (0, 3.902073579310743) 0.21377181121424527\n",
      "HMR_4604 : (0, 6.614268135164198) 0.21377181121424524\n",
      "HMR_4304 : (0, 4.750606504835592) 0.21377181121424524\n",
      "HMR_4473 : (0, 6.417515002885087) 0.21377181121424524\n",
      "HMR_4474 : (0, 6.417515002885087) 0.21377181121424524\n",
      "HMR_4168 : (0, 6.420044420354169) 0.21377181121424524\n",
      "HMR_4406 : (0, 3.7441610955704094) 0.08301524119460235\n",
      "HMR_4518 : (0, 3.003602236680196) 0.08301524119460235\n",
      "HMR_4519 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4520 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4600 : (0, 6.241458871274651) 0.08301524119460235\n",
      "HMR_4646 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4648 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4649 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4650 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4664 : (0, 5.174326515173915) 0.08301524119460235\n",
      "HMR_4799 : (0, 5.3384244147835584) 0.08301524119460235\n",
      "HMR_4802 : (0, 5.3384244147835584) 0.08301524119460235\n",
      "HMR_4808 : (0, 4.04176864995163) 0.08301524119460235\n",
      "HMR_4810 : (0, 6.224194663970433) 0.08301524119460235\n",
      "HMR_6601 : (0, 0.1243281350022017) 0.08301524119460235\n",
      "HMR_8755 : (0, 0.7990873060740036) 0.08301524119460235\n",
      "HMR_4211 : (0, 6.420044420354169) 0.08301524119460235\n",
      "HMR_4343 : (0, 2.673556423990145) 0.08301524119460235\n",
      "HMR_4470 : (0, 0.0976107966264223) 0.08301524119460235\n",
      "HMR_4471 : (0, 0.0976107966264223) 0.08301524119460235\n",
      "HMR_4472 : (0, 0.0976107966264223) 0.08301524119460235\n",
      "HMR_4513 : (0, 3.4462562298895643) 0.08301524119460235\n",
      "HMR_4736 : (0, 0.0) 0.08301524119460235\n",
      "HMR_4819 : (0, 0.0) 0.08301524119460235\n",
      "HMR_6623 : (0, 5.597531174224212) 0.08301524119460235\n",
      "HMR_6624 : (0, 2.169925001442312) 0.08301524119460235\n",
      "HMR_3965 : (0, 5.9368734618242325) 0.08301524119460235\n",
      "HMR_3966 : (0, 6.420044420354169) 0.08301524119460235\n",
      "HMR_4054 : (0, 5.597531174224212) 0.08301524119460235\n",
      "HMR_4483 : (0, 2.169925001442312) 0.08301524119460235\n",
      "HMR_4507 : (0, 5.385776138269413) 0.08301524119460235\n",
      "HMR_4516 : (0, 5.519793486241101) 0.08301524119460235\n",
      "HMR_4601 : (0, 6.241458871274651) 0.08301524119460235\n",
      "HMR_4633 : (0, 2.114367024952) 0.08301524119460235\n",
      "HMR_4641 : (0, 5.597531174224212) 0.08301524119460235\n",
      "HMR_4806 : (0, 5.3384244147835584) 0.08301524119460235\n",
      "HMR_6625 : (0, 2.169925001442312) 0.08301524119460235\n",
      "HMR_7879 : (0, 6.420044420354169) 0.08301524119460235\n",
      "HMR_7880 : (0, 3.3868109464722167) 0.08301524119460235\n",
      "HMR_8446 : (0, 0.1243281350022017) 0.08301524119460235\n",
      "HMR_8473 : (0, 2.114367024952) 0.08301524119460235\n",
      "HMR_8480 : (0, 0.1243281350022017) 0.08301524119460235\n",
      "HMR_8483 : (0, 5.9368734618242325) 0.08301524119460235\n",
      "HMR_8488 : (0, 6.420044420354169) 0.08301524119460235\n",
      "HMR_8489 : (0, 6.420044420354169) 0.08301524119460235\n",
      "HMR_8493 : (0, 3.399171093819823) 0.08301524119460235\n",
      "HMR_8494 : (0, 3.399171093819823) 0.08301524119460235\n",
      "HMR_8495 : (0, 3.399171093819823) 0.08301524119460235\n",
      "HMR_3811 : (0, 6.629648044187436) 0.08301524119460235\n",
      "HMR_3822 : (0, 1.989139007368233) 0.08301524119460235\n",
      "HMR_3831 : (0, 5.747924416238441) 0.08301524119460191\n",
      "HMR_3865 : (0, 4.795974694206668) 0.08301524119460191\n",
      "HMR_3870 : (0, 3.953265239014844) 0.08301524119460191\n",
      "HMR_3873 : (0, 1.292781749227846) 0.08301524119460191\n",
      "HMR_8654 : (0, 1.292781749227846) 0.08301524119460191\n",
      "HMR_3892 : (0, 7.128767676685553) 0.08301524119460191\n",
      "HMR_9802 : (0, 0.4436066514756146) 0.08301524119460191\n",
      "HMR_3903 : (0, 4.938285791884053) 0.08301524119460191\n",
      "HMR_4114 : (0, 4.28021399581062) 0.08301524119460191\n",
      "HMR_4115 : (0, 4.28021399581062) 0.08301524119460191\n",
      "HMR_4118 : (0, 3.953265239014844) 0.08301524119460191\n",
      "HMR_4196 : (0, 2.5360529002402097) 0.08301524119460191\n",
      "HMR_4287 : (0, 7.399342019125501) 0.08301524119460191\n",
      "HMR_7641 : (0, 0.1243281350022017) 0.08301524119460191\n",
      "HMR_8626 : (0, 2.941106310946432) 0.08301524119459813\n",
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      "HMR_2171 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2174 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2175 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2176 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2179 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2180 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2181 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_4295 : (0, 0.879705766282288) 0.08301524119460765\n",
      "HMR_2227 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2228 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2229 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2230 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2231 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2232 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2233 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2234 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2235 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2236 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2237 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2238 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2239 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2240 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2241 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2242 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2243 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2244 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2245 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2246 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2247 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2249 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2250 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2251 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2252 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2254 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2255 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2256 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2257 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_2307 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2317 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2326 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2334 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2343 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2348 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2354 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2362 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2191 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2202 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2208 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2212 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2217 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2260 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2264 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2268 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2270 : (0, 7.005736816813163) 0.08301524119460765\n",
      "HMR_2150 : (0, 6.359486030311388) 0.08301524119460765\n",
      "HMR_6398 : (0, 2.724650271732968) 0.08301524119460765\n",
      "HMR_6399 : (0, 2.724650271732968) 0.08301524119460765\n",
      "HMR_6401 : (0, 2.097610796626422) 0.08301524119460765\n",
      "HMR_6402 : (0, 2.097610796626422) 0.08301524119460765\n",
      "HMR_6403 : (0, 2.485426827170241) 0.08301524119460765\n",
      "HMR_2478 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2489 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2499 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2516 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2524 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2533 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2541 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2544 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2561 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2565 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2568 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2572 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2578 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2586 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_2387 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2397 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2417 : (0, 5.017031080527841) 0.08301524119460765\n",
      "HMR_2426 : (0, 5.017031080527841) 0.08301524119460765\n",
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      "HMR_0958 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0959 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0961 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0964 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0967 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0971 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0976 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0998 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_0999 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1000 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1013 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1014 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1015 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1016 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1017 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1018 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1029 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1030 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1033 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1034 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1037 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1039 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1062 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1063 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1064 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1073 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1075 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1077 : (0, 0.1110313123887439) 0.08301524119460765\n",
      "HMR_1079 : (0, 2.0669502439246266) 0.08301524119460765\n",
      "HMR_1081 : (0, 0.1505596765753814) 0.08301524119460765\n",
      "HMR_8545 : (0, 0.070389327891398) 0.08301524119460765\n",
      "HMR_8550 : (0, 0.1505596765753814) 0.08301524119460765\n",
      "HMR_8554 : (0, 0.01435529297707) 0.08301524119460765\n",
      "HMR_8555 : (0, 0.0) 0.08301524119460765\n",
      "HMR_8556 : (0, 0.01435529297707) 0.08301524119460765\n",
      "HMR_3475 : (0, 4.772413554748482) 0.08301524119460765\n",
      "HMR_2825 : (0, 2.127633279725874) 0.08301524119460765\n",
      "HMR_2829 : (0, 2.127633279725874) 0.08301524119460765\n",
      "HMR_2830 : (0, 2.879705766282288) 0.08301524119460765\n",
      "HMR_2833 : (0, 2.127633279725874) 0.08301524119460765\n",
      "HMR_2834 : (0, 2.879705766282288) 0.08301524119460765\n",
      "HMR_0002 : (0, 0.0565835283663675) 0.08301524119460765\n",
      "HMR_0449 : (0, 5.233811384293157) 0.08301524119460765\n",
      "HMR_7588 : (0, 4.837438714856374) 0.08301524119460765\n",
      "HMR_3484 : (0, 1.989139007368233) 0.08301524119460765\n",
      "HMR_3488 : (0, 1.989139007368233) 0.08301524119460765\n",
      "HMR_3511 : (0, 2.7311832415722) 0.08301524119460765\n",
      "HMR_3156 : (0, 1.613531652917927) 0.08301524119460765\n",
      "HMR_3202 : (0, 1.613531652917927) 0.08301524119460765\n",
      "HMR_3526 : (0, 2.7311832415722) 0.08301524119460765\n",
      "HMR_1573 : (0, 0.01435529297707) 0.08301524119460432\n",
      "HMR_6908 : (0, 4.161887682376894) 0.08301524119460432\n",
      "HMR_7167 : (0, 4.836934011321092) 0.08301524119460432\n",
      "HMR_7168 : (0, 4.611172380044005) 0.08301524119460432\n",
      "HMR_7170 : (0, 4.161081482277184) 0.08301524119460432\n",
      "HMR_9722 : (0, 5.727103603522661) 0.08301524119460432\n",
      "HMR_1920 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_1928 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_1929 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_1932 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_1933 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_1934 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_1935 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_1940 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_1943 : (0, 0.01435529297707) 0.08301524119460432\n",
      "HMR_1948 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_1990 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_1991 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_1992 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_2005 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_2007 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_2010 : (0, 0.0) 0.08301524119460432\n",
      "HMR_2011 : (0, 0.0) 0.08301524119460432\n",
      "HMR_6793 : (0, 0.1110313123887439) 0.08301524119460432\n",
      "HMR_6794 : (0, 0.1110313123887439) 0.08301524119460432\n",
      "HMR_6795 : (0, 0.1110313123887439) 0.08301524119460432\n",
      "HMR_6796 : (0, 0.1110313123887439) 0.08301524119460432\n",
      "HMR_7928 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_7932 : (0, 2.639232163249277) 0.08301524119460432\n",
      "HMR_7934 : (0, 0.0) 0.08301524119460432\n",
      "HMR_7935 : (0, 0.1243281350022017) 0.08301524119460432\n",
      "HMR_7936 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_7937 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_7938 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_7945 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_7948 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_7950 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_7952 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_7970 : (0, 4.308885057411763) 0.08301524119460432\n",
      "HMR_7974 : (0, 0.0) 0.08301524119460432\n",
      "HMR_7976 : (0, 0.8399595874895318) 0.08301524119460432\n",
      "HMR_7978 : (0, 0.0) 0.08301524119460432\n",
      "HMR_1944 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_1945 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_1952 : (0, 0.0426443374084937) 0.08301524119460432\n",
      "HMR_1953 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_1958 : (0, 0.0285691521967709) 0.08301524119460432\n",
      "HMR_1962 : (0, 0.0426443374084937) 0.08301524119460432\n",
      "HMR_1963 : (0, 0.918386234446348) 0.08301524119460432\n",
      "HMR_1969 : (0, 0.6690267655096305) 0.08301524119460432\n",
      "HMR_1477 : (0, 5.859969548221026) 0.08301524119460432\n",
      "HMR_1478 : (0, 5.859969548221026) 0.08301524119460432\n",
      "HMR_1479 : (0, 5.859969548221026) 0.08301524119460432\n",
      "HMR_1509 : (0, 4.308885057411763) 0.08301524119460432\n",
      "HMR_1516 : (0, 5.73579292798531) 0.08301524119460432\n",
      "HMR_1557 : (0, 5.73579292798531) 0.08301524119460432\n",
      "HMR_1558 : (0, 5.73579292798531) 0.08301524119460432\n",
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      "HMR_1538 : (0, 5.859969548221026) 0.08301524119460432\n",
      "HMR_1539 : (0, 5.859969548221026) 0.08301524119460432\n",
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      "HMR_2047 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2049 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2050 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2051 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2055 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2056 : (0, 0.0285691521967709) 0.08301524119461971\n",
      "HMR_2057 : (0, 0.0285691521967709) 0.08301524119461971\n",
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      "HMR_8169 : (0, 1.263034405833794) 0.08301524119461898\n",
      "HMR_8170 : (0, 1.263034405833794) 0.08301524119461898\n",
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      "HMR_8173 : (0, 1.263034405833794) 0.08301524119461898\n",
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      "HMR_8176 : (0, 1.263034405833794) 0.08301524119461898\n",
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      "HMR_8180 : (0, 0.137503523749935) 0.08301524119461898\n",
      "HMR_8181 : (0, 0.137503523749935) 0.08301524119461898\n",
      "HMR_8182 : (0, 0.137503523749935) 0.08301524119461898\n",
      "HMR_8183 : (0, 0.137503523749935) 0.08301524119461898\n",
      "HMR_8184 : (0, 4.1001366712854495) 0.08301524119461898\n",
      "HMR_8185 : (0, 1.263034405833794) 0.08301524119461898\n",
      "HMR_8186 : (0, 1.263034405833794) 0.08301524119461898\n",
      "HMR_8187 : (0, 1.263034405833794) 0.08301524119461898\n",
      "HMR_8190 : (0, 1.0426443374084935) 0.08301524119461898\n",
      "HMR_8191 : (0, 1.0426443374084935) 0.08301524119461898\n",
      "HMR_8192 : (0, 1.0426443374084935) 0.08301524119461898\n",
      "HMR_8194 : (0, 1.263034405833794) 0.08301524119461898\n",
      "HMR_8198 : (0, 0.5360529002402097) 0.08301524119461898\n",
      "HMR_8201 : (0, 2.910732661902913) 0.08301524119461898\n",
      "HMR_8206 : (0, 1.15704371014558) 0.08301524119461898\n",
      "HMR_8209 : (0, 3.6392321632492775) 0.08301524119461898\n",
      "HMR_8210 : (0, 4.008092420948722) 0.08301524119461898\n",
      "HMR_8211 : (0, 5.478324711485028) 0.08301524119461898\n",
      "HMR_8212 : (0, 1.15704371014558) 0.08301524119461898\n",
      "HMR_8217 : (0, 4.2471680003747725) 0.08301524119461898\n",
      "HMR_8224 : (0, 3.428946344769483) 0.08301524119461898\n",
      "HMR_8226 : (0, 3.428946344769483) 0.08301524119461898\n",
      "HMR_8227 : (0, 3.428946344769483) 0.08301524119461898\n",
      "HMR_8228 : (0, 3.428946344769483) 0.08301524119461898\n",
      "HMR_8233 : (0, 1.063502942306158) 0.08301524119461898\n",
      "HMR_8235 : (0, 1.063502942306158) 0.08301524119461898\n",
      "HMR_8237 : (0, 3.111031312388744) 0.08301524119461898\n",
      "HMR_8238 : (0, 3.111031312388744) 0.0830152411946118\n",
      "HMR_8242 : (0, 0.6780719051126377) 0.0830152411946118\n",
      "HMR_8248 : (0, 4.000901402741532) 0.0830152411946118\n",
      "HMR_8249 : (0, 1.263034405833794) 0.0830152411946118\n",
      "HMR_8250 : (0, 1.263034405833794) 0.0830152411946118\n",
      "HMR_8251 : (0, 1.263034405833794) 0.0830152411946118\n",
      "HMR_0673 : (0, 4.127633279725874) 0.0830152411946118\n",
      "HMR_0674 : (0, 4.127633279725874) 0.0830152411946118\n",
      "HMR_0675 : (0, 4.127633279725874) 0.0830152411946118\n",
      "HMR_0676 : (0, 4.127633279725874) 0.0830152411946118\n",
      "HMR_0677 : (0, 4.127633279725874) 0.08301524119459697\n",
      "HMR_0678 : (0, 4.127633279725874) 0.08301524119458752\n",
      "HMR_4296 : (0, 0.1890338243900171) 0.08301524119458752\n",
      "HMR_0478 : (0, 0.2265085298086797) 0.08301524119458752\n",
      "HMR_0483 : (0, 5.233811384293157) 0.08301524119458752\n",
      "HMR_0482 : (0, 5.233811384293157) 0.08301524119458752\n",
      "HMR_0610 : (0, 5.1039172107520665) 0.08301524119458752\n",
      "HMR_0613 : (0, 5.1039172107520665) 0.08301524119458752\n",
      "HMR_0616 : (0, 4.019701914442548) 0.08301524119458752\n",
      "HMR_0622 : (0, 2.8094144442358986) 0.08301524119458752\n",
      "HMR_0623 : (0, 3.959770155211468) 0.08301524119458752\n",
      "HMR_0627 : (0, 4.019701914442548) 0.08301524119458752\n",
      "HMR_0634 : (0, 2.2957230245399685) 0.08301524119458752\n",
      "HMR_0635 : (0, 2.575312330687437) 0.08301524119458752\n",
      "HMR_0640 : (0, 0.0565835283663675) 0.08301524119458752\n",
      "HMR_0646 : (0, 2.575312330687437) 0.08301524119458752\n",
      "HMR_0649 : (0, 0.8237493603082727) 0.08301524119460364\n",
      "HMR_0651 : (0, 4.493775408460703) 0.08301524119460364\n",
      "HMR_0653 : (0, 3.636914580355878) 0.08301524119460364\n",
      "HMR_0654 : (0, 3.636914580355878) 0.08301524119460364\n",
      "HMR_0657 : (0, 3.636914580355878) 0.08301524119460364\n",
      "HMR_4627 : (0, 0.9708536543404837) 0.08301524119460364\n",
      "HMR_4838 : (0, 0.9708536543404837) 0.08301524119460364\n",
      "HMR_4839 : (0, 0.9708536543404837) 0.08301524119460364\n",
      "HMR_7594 : (0, 4.434294617959925) 0.08301524119460364\n",
      "HMR_7612 : (0, 0.0) 0.08301524119460364\n",
      "HMR_7755 : (0, 4.249445341085838) 0.08301524119460364\n",
      "HMR_8424 : (0, 0.8237493603082727) 0.08301524119460364\n",
      "HMR_8519 : (0, 0.0) 0.08301524119460364\n",
      "HMR_9805 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0815 : (0, 1.0426443374084935) 0.08301524119460364\n",
      "HMR_0816 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0820 : (0, 4.1001366712854495) 0.08301524119460364\n",
      "HMR_0822 : (0, 0.137503523749935) 0.08301524119460364\n",
      "HMR_0824 : (0, 4.1001366712854495) 0.08301524119460364\n",
      "HMR_0827 : (0, 1.0426443374084935) 0.08301524119460364\n",
      "HMR_0829 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0839 : (0, 0.137503523749935) 0.08301524119460364\n",
      "HMR_0840 : (0, 3.187451054027326) 0.08301524119460364\n",
      "HMR_0841 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0842 : (0, 1.0426443374084935) 0.08301524119460364\n",
      "HMR_0843 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0846 : (0, 0.137503523749935) 0.08301524119460364\n",
      "HMR_0848 : (0, 3.187451054027326) 0.08301524119460364\n",
      "HMR_0851 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0852 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0853 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0854 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0856 : (0, 1.0426443374084935) 0.08301524119460364\n",
      "HMR_0857 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0858 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0801 : (0, 1.5897634869849773) 0.08301524119460364\n",
      "HMR_0803 : (0, 4.2471680003747725) 0.08301524119460364\n",
      "HMR_0805 : (0, 1.0908534304511135) 0.08301524119460364\n",
      "HMR_0806 : (0, 1.0908534304511135) 0.08301524119460364\n",
      "HMR_0809 : (0, 0.0285691521967709) 0.08301524119460364\n",
      "HMR_0810 : (0, 0.5360529002402097) 0.08301524119460364\n",
      "HMR_0811 : (0, 2.910732661902913) 0.08301524119460364\n",
      "HMR_0814 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0859 : (0, 0.1890338243900171) 0.08301524119460364\n",
      "HMR_0865 : (0, 0.5360529002402097) 0.08301524119460364\n",
      "HMR_0867 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0868 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0876 : (0, 1.0356239097307212) 0.08301524119460364\n",
      "HMR_0877 : (0, 0.0) 0.08301524119460364\n",
      "HMR_0879 : (0, 0.5360529002402097) 0.08301524119460364\n",
      "HMR_0881 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0884 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0887 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0892 : (0, 1.263034405833794) 0.08301524119460364\n",
      "HMR_0901 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0902 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0905 : (0, 0.3561438102252753) 0.08301524119460364\n",
      "HMR_0906 : (0, 4.234194722953812) 0.08301524119460364\n",
      "HMR_0910 : (0, 1.0356239097307212) 0.08301524119460364\n"
     ]
    }
   ],
   "source": [
    "one_gene_constrained_reactions = {} #create dictionary to contain reaction bounds, according to code below\n",
    "                                    #this dictionary will be used by MEWpy to constrain model \n",
    "for r in one_gene_forward:\n",
    "    if r not in media.keys(): #do not overwrite media conditions\n",
    "        if r not in media_only_essential_reactions: #do not constrain essential reactions/genes, or growth will be blocked\n",
    "            if model.reactions.get_by_id(r).gene_reaction_rule not in media_only_essential_genes:\n",
    "                if model.reactions.get_by_id(r).gene_reaction_rule in gene_exp_dict.keys(): #check we have expression data\n",
    "                    if gene_exp_dict[model.reactions.get_by_id(r).gene_reaction_rule] != (0,0):\n",
    "                        model.reactions.get_by_id(r).bounds = (0,(gene_exp_dict[model.reactions.get_by_id(r).gene_reaction_rule])) #set upper bound equal to expression value\n",
    "                        solution = model.optimize() #optimise after constraint, using COBRApy\n",
    "                        if solution.fluxes['biomass_human'] <= 0: #enforce experimental growth value as minimum gorwth rates constraints can reach\n",
    "                            print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                            model.reactions.get_by_id(r).bounds = (0,1000) #if growth is constrained below experimental, then reopen reaction\n",
    "                            solution = model.optimize()\n",
    "                            print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                            one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds #save reaction bounds to dictionary\n",
    "                        if solution.fluxes['biomass_human'] != 0:\n",
    "                            if solution.fluxes['biomass_human'] > 0:\n",
    "                                print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds #use expression data as reaction bound, if it doesn't fall below experimental\n",
    "                            \n",
    "for r in one_gene_reversible: #run constraints code for reversible, one-gene reactions\n",
    "    if r not in media.keys():\n",
    "        if r not in media_only_essential_reactions: #change to new dict\n",
    "            if model.reactions.get_by_id(r).gene_reaction_rule not in media_only_essential_reactions:\n",
    "                if model.reactions.get_by_id(r).gene_reaction_rule in gene_exp_dict.keys(): \n",
    "                    if gene_exp_dict[model.reactions.get_by_id(r).gene_reaction_rule] != (0,0): \n",
    "                        #here, set lower bound as -1*expression value, and upper bound as positive expression value\n",
    "                        model.reactions.get_by_id(r).bounds = (-1*(gene_exp_dict[model.reactions.get_by_id(r).gene_reaction_rule]),(gene_exp_dict[model.reactions.get_by_id(r).gene_reaction_rule]))\n",
    "                        solution = model.optimize()\n",
    "                        if solution.fluxes['biomass_human'] <= 0:\n",
    "                            print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                            model.reactions.get_by_id(r).bounds = (-1000,1000)\n",
    "                            solution = model.optimize()\n",
    "                            print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                            #update constraints dictionary with reversible reaction bounds\n",
    "                            one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "                        if solution.fluxes['biomass_human'] != 0:\n",
    "                            if solution.fluxes['biomass_human'] > 0:\n",
    "                                print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "                            \n",
    "or_forward = []\n",
    "or_reversible = []\n",
    "for r in ORs:\n",
    "    if model.reactions.get_by_id(r).reversibility == True:\n",
    "        or_reversible.append(r)\n",
    "    else:\n",
    "        or_forward.append(r)\n",
    "print('number of reversible, OR reactions =', len(or_reversible))\n",
    "print('number of forward, OR reactions =', len(or_forward))\n",
    "\n",
    "for r in or_forward:\n",
    "    if r not in media.keys():\n",
    "        if r not in media_only_essential_reactions:\n",
    "            rule_list = [] #make list to append with terms in reaction rule\n",
    "            rule = model.reactions.get_by_id(r).gene_reaction_rule\n",
    "            rule_list.append(rule.split())\n",
    "            rule_genes = [] #append new list with only ensembl IDs from reaction rule\n",
    "            for n in rule_list:\n",
    "                for num in n:\n",
    "                    if 'ENS' in num:\n",
    "                        rule_genes.append(num)\n",
    "            #calculate sum of expressions\n",
    "            genes_in_dataset = []\n",
    "            for gene in rule_genes:\n",
    "                if gene in gene_exp_dict.keys():\n",
    "                    genes_in_dataset.append(gene)\n",
    "            exp_list = []        \n",
    "            for g in genes_in_dataset:\n",
    "                exp_list.append(gene_exp_dict[g])\n",
    "            sum_of_expressions = sum(exp_list)\n",
    "            #set bounds according to sum of expressions\n",
    "            model.reactions.get_by_id(r).bounds = (0,sum_of_expressions) #same as 'one-gene' method, where expression (sum) is upper bound\n",
    "            solution = model.optimize()\n",
    "            if solution.fluxes['biomass_human'] <= 0:\n",
    "                print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                model.reactions.get_by_id(r).bounds = (0,1000)\n",
    "                solution = model.optimize()\n",
    "                print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "            if solution.fluxes['biomass_human'] != 0:\n",
    "                if solution.fluxes['biomass_human'] > 0:\n",
    "                    print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                    one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "                \n",
    "for r in or_reversible:\n",
    "    if r not in media.keys():\n",
    "        if r not in media_only_essential_reactions:\n",
    "            #find ensembl ids in gene-reaction rules\n",
    "            rule_list = []\n",
    "            rule = model.reactions.get_by_id(r).gene_reaction_rule\n",
    "            rule_list.append(rule.split())\n",
    "            rule_genes = []\n",
    "            for n in rule_list:\n",
    "                for num in n:\n",
    "                    if 'ENS' in num:\n",
    "                        rule_genes.append(num)\n",
    "            #calculate sum of expressions\n",
    "            genes_in_dataset = []\n",
    "            for gene in rule_genes:\n",
    "                if gene in gene_exp_dict.keys():\n",
    "                    genes_in_dataset.append(gene)\n",
    "            exp_list = []        \n",
    "            for g in genes_in_dataset:\n",
    "                exp_list.append(gene_exp_dict[g])\n",
    "            sum_of_expressions = sum(exp_list)\n",
    "            #set bounds according to sum of expressions; same as before, use negative and positive expression (sum) as bounds\n",
    "            model.reactions.get_by_id(r).bounds = (-1*sum_of_expressions,sum_of_expressions)\n",
    "            solution = model.optimize()\n",
    "            if solution.fluxes['biomass_human'] <= 0:\n",
    "                print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                model.reactions.get_by_id(r).bounds = (-1000,1000)\n",
    "                solution = model.optimize()\n",
    "                print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "            if solution.fluxes['biomass_human'] != 0:\n",
    "                if solution.fluxes['biomass_human'] > 0:\n",
    "                    print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                    one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "                \n",
    "and_forward = []\n",
    "and_reversible = []\n",
    "for r in ANDs:\n",
    "    if model.reactions.get_by_id(r).reversibility == True:\n",
    "        and_reversible.append(r)\n",
    "    else:\n",
    "        and_forward.append(r)\n",
    "print('number of reversible, AND reactions =', len(and_reversible))\n",
    "print('number of forward, AND reactions =', len(and_forward))\n",
    "\n",
    "for r in and_forward:\n",
    "    if r not in media.keys():\n",
    "        if r not in media_only_essential_reactions:\n",
    "            #find ensembl IDs in reaction rules, as performed for 'or' rules\n",
    "            rule_list = []\n",
    "            rule = model.reactions.get_by_id(r).gene_reaction_rule\n",
    "            rule_list.append(rule.split())\n",
    "            rule_genes = []\n",
    "            for n in rule_list:\n",
    "                for num in n:\n",
    "                    if 'ENS' in num:\n",
    "                        rule_genes.append(num)\n",
    "            #generate list of expressions\n",
    "            genes_in_dataset = []\n",
    "            for gene in rule_genes:\n",
    "                if gene in gene_exp_dict.keys():\n",
    "                    genes_in_dataset.append(gene)\n",
    "            exp_list = []        \n",
    "            for g in genes_in_dataset:\n",
    "                exp_list.append(gene_exp_dict[g])\n",
    "            if len(exp_list) > 1:\n",
    "                exp_list.sort()\n",
    "                min_expression = exp_list[0]\n",
    "            if len(exp_list) == 1:\n",
    "                min_expression = exp_list[0] #set variable for minimum, rate-limiting subunit expression\n",
    "            #use minimum expression as upper bound for forward reactions\n",
    "            model.reactions.get_by_id(r).bounds = (0,min_expression)\n",
    "            solution = model.optimize()\n",
    "            if solution.fluxes['biomass_human'] <= 0:\n",
    "                print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                model.reactions.get_by_id(r).bounds = (0,1000)\n",
    "                solution = model.optimize()\n",
    "                print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "            if solution.fluxes['biomass_human'] != 0:\n",
    "                if solution.fluxes['biomass_human'] > 0:\n",
    "                    print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                    one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "for r in and_reversible:\n",
    "    if r not in media.keys():\n",
    "        if r not in media_only_essential_reactions:\n",
    "            rule_list = []\n",
    "            rule = model.reactions.get_by_id(r).gene_reaction_rule\n",
    "            rule_list.append(rule.split())\n",
    "            rule_genes = []\n",
    "            for n in rule_list:\n",
    "                for num in n:\n",
    "                    if 'ENS' in num:\n",
    "                        rule_genes.append(num)\n",
    "            #generate list of expressions\n",
    "            genes_in_dataset = []\n",
    "            for gene in rule_genes:\n",
    "                if gene in gene_exp_dict.keys():\n",
    "                    genes_in_dataset.append(gene)\n",
    "            exp_list = []        \n",
    "            for g in genes_in_dataset:\n",
    "                exp_list.append(gene_exp_dict[g])\n",
    "            if len(exp_list) > 1:\n",
    "                exp_list.sort()\n",
    "                min_expression = exp_list[0]\n",
    "            if len(exp_list) == 1:\n",
    "                min_expression = exp_list[0]\n",
    "            #set bounds according to minimum expression; use negative and positive expression (minimum) as bounds\n",
    "            model.reactions.get_by_id(r).bounds = ((-1*min_expression),min_expression)\n",
    "            solution = model.optimize()\n",
    "            if solution.fluxes['biomass_human'] <= 0:\n",
    "                print(r, ':', 'constrained bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                model.reactions.get_by_id(r).bounds = (-1000,1000)\n",
    "                solution = model.optimize()\n",
    "                print(r, ':', 're-opened bounds', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "            if solution.fluxes['biomass_human'] != 0:\n",
    "                if solution.fluxes['biomass_human'] > 0:\n",
    "                    print(r, ':', model.reactions.get_by_id(r).bounds, solution.fluxes['biomass_human'])\n",
    "                    one_gene_constrained_reactions[r] = model.reactions.get_by_id(r).bounds\n",
    "                \n",
    "all_and_simulation = get_simulator(model, envcond = media, constraints = one_gene_constrained_reactions)\n",
    "all_and_result = all_and_simulation.simulate()\n",
    "print('growth with media AND gene expression constraints: ', all_and_result.find(['biomass_human']).iloc[0,0],\n",
    "      'g/gDW/hour','=',(1/all_and_result.find(['biomass_human']).iloc[0,0]),'hours')"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "525b4dc8",
   "metadata": {},
   "outputs": [],
   "source": [
    "cov318_260923_no_thresholds = all_and_result.dataframe #set per cell line\n",
    "%store cov318_260923_no_thresholds #set per cell line"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "be83ceca",
   "metadata": {},
   "outputs": [],
   "source": [
    "model = cov318_260923_model\n",
    "%store cov318_260923_model"
   ]
  },
  {
   "cell_type": "code",
   "execution_count": null,
   "id": "8f1767d4",
   "metadata": {},
   "outputs": [],
   "source": []
  }
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