y_petri 1.0.0

data/lib/y_petri/demonstrator_4.rb

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+#encoding: utf-8
+
+require 'y_petri'
+include YPetri
+require 'sy'
+require 'mathn'
+
+# === General assumptions
+
+Cell_diameter = 10.µm
+Cytoplasm_volume = ( 4 / 3 * Math::PI * ( Cell_diameter / 2 ) ** 3 ).( SY::LitreVolume )
+
+# How many molecules per micromolar are there in an average cell.
+Pieces_per_µM = ( 1.µM * Cytoplasm_volume ).in( :unit )
+
+# === Simulation settings
+
+set_step 60.s.in( :s )
+set_target_time 20.min.in( :s )      # up to 5 days is interesting
+set_sampling 120.s.in( :s )
+
+# === Places (all in µM)
+
+AMP = Place m!: 82.0                     # Traut1994pcp
+ADP = Place m!: 137.0                    # Traut1994pcp
+ATP = Place m!: 2102.0                   # Traut1994pcp
+UTP = Place m!: 253.0                    # Traut1994pcp
+UDP = Place m!: ADP.m / ATP.m * UTP.m
+UMP = Place m!: AMP.m / ATP.m * UTP.m
+GMP = Place m!: 32.0                     # Traut1994pcp
+
+DeoxyATP = Place m!: 2.4                 # Traut1994pcp
+DeoxyADP = Place m!: ADP.m / ATP.m * DeoxyATP.m
+DeoxyAMP = Place m!: AMP.m / ATP.m * DeoxyATP.m
+
+DeoxyCytidine = Place m!: 0.7            # Traut1994pcp
+DeoxyCMP = Place m!: 1.9                 # Traut1994pcp
+DeoxyCDP = Place m!: 0.1                 # Traut1994pcp
+DeoxyCTP = Place m!: 4.5                 # Traut1994pcp
+
+DeoxyGTP = Place m!: 2.7                 # Traut1994pcp
+DeoxyGMP = Place m!: AMP.m / ATP.m * DeoxyATP.m
+
+DeoxyUridine = Place m!: 0.6             # Traut1994pcp
+DeoxyUMP = Place m!: 2.70                # Traut1994pcp
+DeoxyUDP = Place m!: 0.5                 # Traut1994pcp
+DeoxyUTP = Place m!: 0.7                 # Traut1994pcp
+
+DeoxyThymidine = Place m!: 0.5           # Traut1994pcp
+DeoxyTMP = Place m!: 0.0                 # in situ
+DeoxyTDP = Place m!: 2.4                 # Traut1994pcp
+DeoxyTTP = Place m!: 17.0                # Traut1994pcp
+
+# === Empirical places (in arbitrary units)
+
+A_phase = Place m!: 1                    # in situ
+S_phase = Place m!: 1                    # in situ
+Cdc20A = Place m!: 0.0                   # in situ
+
+# === Enzymes
+
+# ==== Thymidine kinase, cytoplasmic (TK1)
+
+# Molecular weight:
+TK1_m = 24.8.kDa
+TK1_a = 9500.mol.min⁻¹.mg⁻¹
+
+# Total unphosphorylated TK1 expressed in <em>monomer molarity</em>.
+TK1 = Place m!: 0                        # in situ
+
+TK1_4mer_Kd = 0.03                       # in situ
+TK1di = Place m!: 0                      # TK1 in the dimer form, unphosphorylated
+TK1di_P = Place m!: 0                    # in situ; TK1 in the dimer form, phosphorylated
+TK1tetra = Place m!: 0                   # TK1 in the tetramer form (phosphorylation prevents 4merization)
+
+# Assignment transition keeping TK1_di level based on total TK1 monomer
+Transition name: :TK1_di_ϝ,
+           assignment: true,
+           domain: TK1,
+           codomain: TK1di,
+           action: lambda { |monomer|    # solution of a quadratic equation for dimer / tetramer balance
+                     TK1_4mer_Kd / 4 * ( ( 1 + 4 / TK1_4mer_Kd * monomer ) ** 0.5 - 1 )
+                   }
+
+# Assignment transition keeping TK1_tetra level based on total TK1 tetramer
+Transition name: :TK1_tetra_ϝ,
+           assignment: true,
+           domain: [ TK1, TK1di ],
+           codomain: TK1tetra,
+           action: lambda { |monomer, dimer| # based on equation monomer = dimer * 2 + tetramer * 4
+             monomer / 4 - dimer / 2
+}
+
+# Dissociation constants [µM]
+
+TK1di_Kd_ATP = 4.7                       # Barroso2003tbd
+TK1di_Kd_dT = 15.0                       # Eriksson2002sfc
+
+# FIXME - THIS IS HOW FAR I CAME
+
+# Inhibition constant of dTTP
+TK1di_Kd_dTTP
+# Hill coefficient of TK1 dimer
+TK1di_hill
+# k_cat of TK1 dimer
+TK1_k_cat = ( TK1_a * TK1_m ).( SY::Amount / SY::Time ).in :s⁻¹
+TK1_k_cat = 3.80                        # 
+
+
+TYMS_m = 66.0.kDa
+RNR_m = 140.0.kDa
+TMPK_m = 50.0.kDa
+
+# === Enzyme specific activities
+
+TK1_a = 5.40.µmol.min⁻¹.mg⁻¹
+TYMS_a = 3.80.µmol.min⁻¹.mg⁻¹
+RNR_a = 1.00.µmol.min⁻¹.mg⁻¹
+TMPK_a = 0.83.µmol.min⁻¹.mg⁻¹
+
+# === Enzyme kcat
+
+TK1_k_cat = ( TK1_a * TK1_m ).( SY::Amount / SY::Time ).in :s⁻¹
+TYMS_k_cat = ( TYMS_a * TYMS_m ).( SY::Amount / SY::Time ).in :s⁻¹
+RNR_k_cat = ( RNR_a * RNR_m ).( SY::Amount / SY::Time ).in :s⁻¹
+TMPK_k_cat = ( TMPK_a * TMPK_m ).( SY::Amount / SY::Time ).in :s⁻¹
+
+# === Clamps (all in µM)
+
+clamp AMP: 8695.0, ADP: 6521.0, ATP: 3152.0
+clamp DeoxyCytidine: 0.5, DeoxyCTP: 1.0, DeoxyGMP: 1.0
+clamp Thymidine: 0.5
+clamp U12P: 2737.0
+
+# === Function closures
+
+# Vmax of an enzyme.
+# 
+Vmax = -> enzyme_µM, k_cat do enzyme_µM * k_cat end
+
+# Michaelis constant reduced for competitive inhibitors.
+# 
+Km_reduced = -> reactant_Km, hash_Ki=Hash.new do
+  hash_Ki.map { |compet_inhibitor_concentration, compet_inhibitor_Ki|
+    compet_inhibitor_concentration / compet_inhibitor_Ki
+  }.reduce( 1, :+ ) * reactant_Km
+end
+
+# Occupancy fraction of the Michaelis-Menten equation.
+# 
+Occupancy = -> reactant_µM, reactant_Km, hash_Ki=Hash.new do
+  reactant_µM / ( reactant_µM + Km_reduced.( reactant_Km, hash_Ki ) )
+end
+
+# Michaelis-Menten equation with competitive inhibitors.
+# 
+MMi = -> reactant_µM, reactant_Km, enzyme_µM, k_cat, hash_Ki=Hash.new do
+  Vmax.( enzyme_µM, k_cat ) * Occupancy.( reactant_µM, reactant_Km, hash_Ki )
+end
+
+# === Michaelis constants (all in µM)
+
+TK1_Thymidine_Km = 5.0
+TYMS_DeoxyUMP_Km = 2.0
+RNR_UDP_Km = 1.0
+TMPK_DeoxyTMP_Km = 12.0
+
+# === DNA synthesis speed
+
+S_phase_duration = 12.h
+Genome_size = 3_000_000_000          # of bases
+DNA_creation_speed = Genome_size / S_phase_duration.in( :s ) # in base.s⁻¹
+
+# === Transitions
+
+Transition name: :TK1_Thymidine_DeoxyTMP,
+           domain: [ Thymidine, TK1, DeoxyT23P, DeoxyCTP, DeoxyCytidine, AMP, ADP, ATP ],
+           stoichiometry: { Thymidine: -1, DeoxyTMP: 1 },
+           rate: proc { |reactant, enzyme, pool, inhibitor_2, inhibitor_3, mono, di, tri|
+             inhibitor_1 = pool * tri / ( di + tri ) # conc. of DeoxyTTP
+             MMi.( reactant, TK1_Thymidine_Km, enzyme, TK1_k_cat,
+                   inhibitor_1 => 13.5, inhibitor_2 => 0.8, inhibitor_3 => 40.0 )
+           }
+
+Transition name: :TYMS_DeoxyUMP_DeoxyTMP,
+           domain: [ DeoxyU12P, TYMS, AMP, ADP, ATP ],
+           stoichiometry: { DeoxyU12P: -1, DeoxyTMP: 1 },
+           rate: proc { |pool, enzyme, mono, di, tri|
+             reactant = pool * di / ( mono + di ) # conc. of DeoxyUMP
+             MMi.( reactant, TYMS_DeoxyUMP_Km, enzyme, TYMS_k_cat )
+           }
+
+Transition name: :RNR_UDP_DeoxyUDP,
+           domain: [ U12P, RNR, DeoxyU12P, AMP, ADP, ATP ],
+           stoichiometry: { U12P: -1, DeoxyU12P: 1 },
+           rate: proc { |pool, enzyme, mono, di, tri|
+             reactant = pool * di / ( mono + di )
+             MMi.( reactant, RNR_UDP_Km, enzyme, RNR_k_cat )
+           }
+
+Transition name: :DNA_polymerase_consumption_of_DeoxyTTP,
+           stoichiometry: { DeoxyT23P: -1 },
+           rate: proc { DNA_creation_speed / 4 }
+
+Transition name: :TMPK_DeoxyTMP_DeoxyTDP,
+           domain: [ DeoxyTMP, TMPK, DeoxyT23P, DeoxyGMP, AMP, ADP, ATP ],
+           stoichiometry: { DeoxyTMP: -1, DeoxyT23P: 1 },
+           rate: proc { |reactant, enzyme, pool, inhibitor_4, mono, di, tri|
+             inhibitor_1 = di
+             inhibitor_2 = pool * di / ( di + tri ) # conc. of DeoxyTDP
+             inhibitor_3 = pool * tri / ( di + tri ) # conc. of DeoxyTTP
+             MMi.( reactant, TMPK_DeoxyTMP_Km, enzyme, TMPK_k_cat )
+           }
+
+# execution
+run!
+plot_recording