'chemesis' is a library of objects for creating models of biochemical reactions, second messengers, and calcium dynamics.
This library is based on chemesis version 2.5, and was developed and contributed to the GENESIS 2.4 libraries by K. T. (Avrama) Blackwell. The main website for the latest chemesis source code, tutorials, simulation scripts, and lecture slides is http://krasnow1.gmu.edu/CENlab/software.html.
Demonstration scripts and tutorials may be found in genesis/Scripts/chemesis. The source code for these objects and their data structure is given in genesis/src/chemesis.
cicr: computes state variables associated with calcium release channels, either the ryanodine or ip3 receptor channel
cicrflux: computes ion flow through ip3 or Ryr receptor channel from the smooth endoplasmic reticulum (SER) and the cytosol.
conservepool: calculates concentration & quantity in a compartment by subtracting the conc/quantity of all other forms of the molecule
diffusion: calculates flux across the shared/connected surface areas
enzyme: implements a reaction pool, and the two coupled reactions implementing and enzyme reaction
feedback: calculates enhancement or reduction in an enzyme activity by another substrance
mmenz: simplified michaelis-menton enzyme reaction
mmpump2: Michaelis-Menten pump. unlike mmpump, this object calculates flux due to the pump
ncx: implements two different forms of a sodium-calcium exchanger
reaction: computes kf*substrates and kb*products for nth order reactions.
rhodopsin: quite a complicated object for calculating stochastic activation and inactivation of rhodopsin molecules
rxnpool: accumulates changes in quantity and concentration from many other chemesis objects and then calculates the new concentration This object is similar to pool (kinetikit) and functions similar to compartment, which accumulates current fluxes.
wgtavg: An object to calculate a weighted average, such as mean calcium in a set of shells.
Note that chemesis does not require you to work in SI units, but if you don't, you need to set various units fields on all the objects, and you must use a set of consistent units.
Object Type: cicr datatype IP3R_type function cicrpool() class [ gate ] [ segment ] size 224 bytes author A. Blackwell ERIM Aug 96; revised GMU Aug 99
VALID ACTIONS
CHECK RESET PROCESS INIT
VALID MESSAGES
[5] CONSERVE xconc /* fraction of other states */
[4] CALCIUM caconc /* concentration of calcium */
[3] IP3 ip3conc /* concentration of ip3 */
[2] GSTATE kbgamma conc /* back rate const and conc in gamma dir */
[1] BSTATE kbbeta conc /* back rate const and conc in beta dir */
[0] ASTATE kbalpha conc /* back rate const and conc in alpha dir */
FIELDS
activation
fraction fraction of channel in state
previous_state
alpha forward rate constant in alpha direction
beta forward rate constant in beta direction
gamma forward rate constant in gamma direction
alpha_state if ip3 is bound (1) or not (0) for this state
beta_state if calcium is bound (1) or not (0) to open part for this state
gamma_state if calcium is bound(1) or not (0) to closed part for this state
conserve flag indicating a conserve pool
xinit initial value
xmin minimum value, typically 0
xmax maximum value, typically 1
DESCRIPTION
cicr computes state variables associated with calcium release channels, either the ryanodine or ip3 receptor channel. Create one element for each receptor state, thus ip3 receptor of DeYoung and Keizer requires 8 cicr elements. cicr calculates the fraction of receptors in each state, the flux is calculated using a cicrflux element. Transitions between ASTATE are dependent on IP3 concentration (a required message for cicr) thus only BSTATE and GSTATE elements, which transitions are calcium dependent, are created for ryanodine receptor channel.
Object Type: cicrflux datatype flux_type function cicrflux() class [ channel ] [ segment ] size 184 bytes author A. Blackwell ERIM Aug 96; revised GMU Dec 99; GMU Mar 02
VALID ACTIONS
CHECK RESET PROCESS INIT
VALID MESSAGES
[2] IP3R ip3r //fraction of open channels
[1] CONC2 conc2
[0] CONC1 conc1
FIELDS
activation
maxflux single channel flux (cm/time) * number of channels * Surface area (cm^2)
deltaflux1 maxflux*openfraction*(conc1-conc2), send value to A of rxnpool 2
deltaflux2 maxflux*openfraction*(conc2-conc1), send value to A of rxnpool 1
power exponent; fraction open = ip3r^power
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
DESCRIPTION
cicrflux computes ion flow through ip3 or Ryr receptor channel from the smooth endoplasmic reticulum (SER) and the cytosol. This requires at least two rxnpools, one tracking calcium in the SER and one tracking calcium in the cytosol. All three messages are required. the IP3R message is really just the fraction field from whichever cicr element is the conducting state
return messages as follows:
addmsg from cicrflux object to pool 1 RXN0MOLES deltaflux2
addmsg from cicrflux object to pool 2 RXN0MOLES deltaflux1
Object Type: conservepool datatype conserve_type function conservepool() class [ concentration ] [ segment ] size 248 bytes author A. Blackwell ERIM Aug 96; revised GMU Dec 99; GMU Mar 02
VALID ACTIONS
CHECK RESET PROCESS INIT
VALID MESSAGES
[2] VOLUME volume /* volume of compartment */
[1] MOLES moles /* quantity of other forms */
[0] CONC conc /* concentration of other forms */
FIELDS
activation
previous_state
Conc concentration of molecule
quantity quantity of molecules
Qinit initial quantity of molecule
Qtot total quantity of this and other forms of molecule
Cinit initial concentration
Cmin minimum concentration
Ctot total concentration of this and other forms of molecule
volume used to convert from concentration to quantity and vice versa
type whether specifying quantity or concentration of molecule
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
Dunits 1 for meters, 1e-4 for cm, etc
VolUnitConv Dunits^3, converts volume to SI
DESCRIPTION
Implementation of pool for conserved molecules. If type = 0, computes concentration of molecule which is the total conc less the conc in all other states. If type = 1, computes quantity of molecule which is the total quantity less the quantity in all other states. Then computes concentration by dividing by volume.
Object Type: diffusion datatype diffusion_type function diffusion() class [ channel ] [ segment ] size 184 bytes author A. Blackwell GMU Dec 97; revised GMU Dec 99; GMU Mar 02
VALID ACTIONS
CHECK RESET PROCESS INIT
VALID MESSAGES
[1] POOL2 len2 area2 conc2 /* pool 1 dimensions & Conc */
[0] POOL1 len1 area1 conc1 /* pool 2 dimensions & Conc*/
FIELDS
D diffusion constant
difflux1 D*area/len*conc21 send value to A field of pool 2
difflux2 D*area/len*conc2, send value to A field of pool 1
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
Dunits 1 for meters, 1e-4 for cm, etc
DESCRIPTION
Diffusion is an object used to computes flux of molecules due to diffusion through shared surface between two rxnpools. This object can implement both 1-D and 2-D diffusion, and sums the fluxes between each pair of rxnpools. 2D diffusion is implemented among a set of cylindrical shells, with the surface area of the side of the cylinder stored in SAside, and surface area of inside and outside of the shell stored in SAout and SAin of the rxnpool (desribed below). Thus, diffusion helps the rxnpool to implements the equation:
Sum over i (Conc1i-Conc2i)*Mean(area1i,area2i)/((len1i+len2i)/2)
Each diffusion element calculates
(Conc1i-Conc2i)*Mean(area1i,area2i)/((len1i+len2i)/2) for a pair of adjacent
rxnpools. Their shared surface areas do not need to be identical. The mean
surface area is calculated as geometric mean, not arithmetic mean.
Each diffusion needs a pair of messages, one from each rxnpool (pool1 and pool2). Each message must contain the appropriate surface area (i.e. the area of the surface facing the other rxnpool), the length of the rxnpool, and the concentration. Each diffusion object then sends a pair of messages back to the rxnpools,
addmsg diffusionElement pool2 RXN0MOLES difflux2
addmsg diffusionElement pool2 RXN0MOLES difflux1
Object Type: enzyme
datatype enzyme_type function enzyme() class [ segment ] author A. Blackwell ERIM Aug 96; revised GMU Dec 99; revised GMU Mar 02
VALID ACTIONS
CHECK SET RESET PROCESS INIT
VALID MESSAGES
[4] VOLUME vol SAin SAout /* volume and SAin input */
[3] RHODOPSIN mrho vol SAin SAout /* effective rhodopsin, volume and SAin input from rhodopsin */
[2] SUBSTRATE conc /* conc. of substrate */
[1] FEEDBACK feedback rateconst /* concentration of feedback molecule, which rate const to modify. */
[0] ENZ conc /* concentration or quantity of enzyme */
FIELDS
conc concentration (integrated)
quant quantity in molecules
complex_conc
complex_quant
previous_state
Cmin minimum concentration
Cinit initial concentration
Qinit initial quantity in molecules
len length of cylindrical pool
radius radius of cylindrical or spherical pool
vol volume of pool
SAside side surface area of cylinder
SAout outer surface area of spherical shell
SAin inner surface area of spherical shell
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
type whether pool integrates concentration (0) or quantity (1)
kf forward rate constant. Kf units must be consistent with substrate units.
kb backward rate constant. units are per time.
kcat catalytic rate constant. units are per time.
deltacat change in product of whole reaction = kcat*EScomplex
deltaenz change in free enzyme conc = (kb+kcat)*EScomplex
kbprod change in substrate conc = kb * EScomplex conc
kfsubs kf * Enz * Subs
feedback computed feedback value
rateconst which rate const is modified by feedback
fbconc concentration of feedback substance
thresh above or below this no feedback computed.
pow raise fb to this power
form 0 for hyperbolic, 1 for sigmoid increase, 2 for sigmoid decrease
sign -1 for feedback below threshold, +1 for fb above thresh
halfmax parameter for sigmoid form of feedback
Dunits 1 for meters, 1e-4 for cm, etc
VolUnitConv Dunits^3, converts volume to SI units
DESCRIPTION
enzyme implements a reaction pool (thus has many of the same fields as rxnpool), and the two reactions of an enzyme reaction. In the first reaction, enzyme binds to substrate. In the second reaction, product is formed and the enzyme is regenerated. Thus, this object tracks the enzyme concentration, but two additional rxnpools are needed - one for substrate and one for product.
Eqn: Michaelis-Menton enzyme kinetics. Vmax = kcat; Km = (Kcat+kb)/kf
kf kcat
[Enzyme] + [Substrate] <-> [E-S] -> [Enzyme] + [Product]
kb
Computes dprod/dt = kcat*E-Scomplex
Solves for E-Scomplex concentration from: dES/dt = -(kcat+kb)*ES + kf*E*S
dProduct/dt units are quantity (not concentration)
addmsg from enz object to rxnpool RXN0MOLES product.
It also has fields to allow modulation (change in rate constants) of the enzyme activity by any molecule. Feedback message requires feedback concentration and rate const: 0 for kf, 1 for kb, 2 for kcat.
using hyperbolic form: feedback is proportional to: 1 / conc(feedback substance) for negative feedback
feedback is proportional to: conc (feeback substance) for positive feedback.
Sigmoid form: feedback is proportional to: conc/conc + halfmax (for inc feedback)
feedback is proportional to: halfmax / conc + halfmax (for dec feedback)
Object Type: feedback datatype feedback_type function feedback() class [ segment ] size 184 bytes author A. Blackwell GMU feb 02
VALID ACTIONS
SET RESET PROCESS INIT
VALID MESSAGES
[0] CONC conc // concentration of feedback substance
FIELDS
thresh above or below this no feedback computed
pow raise fb to this power
form 0 for hyperbolic, 1 for sigmoid increase, 2 for sigmoid decrease
sign -1 for feedback below threshold, +1 for fb above thresh
halfmax parameter for sigmoid form of feedback
feedback output value of feedback
DESCRIPTION
An object for computing modification of rate constants caused by feedback of some substance, e.g. calcium, sent as message.
hyperbolic form: feedback is proportional to: 1 / conc(feedback substance) for negative feedback
feedback is proportional to: conc (feeback substance) for positive feedback.
Sigmoid form: feedback is proportional to: conc/conc + halfmax (for inc feedback) feedback is proportional to: halfmax / conc + halfmax (for dec feedback)
Object Type: mmenz datatype mmenz_type function mmenz() class [ segment ] size 208 bytes author A. Blackwell ERIM Aug 96; revised GMU Dec 99
VALID ACTIONS
SET RESET PROCESS INIT
VALID MESSAGES
[2] SUBSTRATE conc /* conc. of substrate */
[1] FEEDBACK conc /* conc. of feedback substance */
[0] ENZ conc /* amount of enzyme */
FIELDS
activation
Vmax maximal rate of reaction, units of per time
Km combination rate constant: (kf2+kb1)/kf1
product quantity of product produced. Units will the the same enzyme units
thresh below this conc, positive feedback, above the concentration implement negative feedback
pos_pow raise positive feedback to this power
pos_form 0 for hyperbolic, 1 for sigmoid
pos_halfmax param for sigmoid feedback
neg_pow raise negative feedback to this power
neg_form 0 for hyperbolic, 1 for sigmoid
neg_halfmax parameter for sigmoid feedback
feedback computed value of feedback
subs_rate
DESCRIPTION
Simplified Michaelis-Menton enzyme kinetics. Can assume constant substrate, or can compute effect of substrate on reaction rate. Vmax = kf2; Km = (Kf2+kb1)/kf1
kf1 kf2
[Enzyme] + [Substrate] <-> [E-S] -> [Enzyme] + [Product]
kb1
Under assumptions of M-M dynamics, Solves dprod/dt = kf1*Enzyme*Subs/(Subs + Km)
Vmax units are quantity per time, where quantity units are the same as the enzyme units (input from enzyme rxnpool). Substrate and Km must have units of Conc. Product (quantity units, same as enzyme) = Vmax * E * S/ (S+Km).
Use addmsg from enz object to rxnpool RXN0MOLES product. For more accurate MM kinetics, enzyme OR enz object in kinetikit. Feedback allows decrease in enzyme activity as function of concentration of feedback substance.
hyperbolic form: feedback is proportional to: 1 / conc(feedback substance) for negative feedback
feedback is proportional to: conc (feeback substance) for positive feedback.
Sigmoid form: feedback is proportional to: conc/conc + halfmax (for inc feedback) feedback is proportional to: halfmax / conc + halfmax (for dec feedback)
Object Type: mmpump2 datatype pump_type function mmpump2() class [ channel ] [ segment ] size 200 bytes author A. Blackwell ERIM Aug 96; revised GMU Dec 99; GMU Mar 02
VALID ACTIONS
SET RESET PROCESS INIT
VALID MESSAGES
[0] CONC conc
FIELDS
activation
max_rate Maximum Pump Rate
half_conc concentration at which pump rate is half maximal
half_conc_pow
moles_in State variable for return message to pools
moles_out State variable for return message to pools
power exponent applied to Concentration
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
DESCRIPTION
A Michaelis-Menton type of formulation of pump. Either SERCA ATPase pump or Na-Ca ATPase cytosolic pump. Requires input message in concentration units. Computes right hand side of dC/dt = (+/-)max_rate * Ca^n / (Ca^n + half_conc^n). Output Messages
addmsg from mmpump2 to cytosol-rxnpool RXN0MOLES moles_out.
addmsg from mmpump2 to ER or extracellular rxnpool RXN0MOLES moles_in.
Note that mmpump is another implementation of a Michaelis-Menton pump.
Object Type: ncx datatype exchange_type function ncx() class [ channel ] [ segment ] author A. Blackwell GMU Sept 02
VALID ACTIONS
CHECK SET RESET PROCESS INIT
VALID MESSAGES
[4] VM Vm /* membrane potential*/
[3] NAEXT conc /* Na external Concentration */
[2] NAINT conc /* Na internal Concentration */
[1] CAEXT conc /* Ca external Concentration */
[0] CAINT conc /* Ca internal concentration */
FIELDS
activation
Ca_int internal calcium concentration
Ca_ext external calcium concentration
Na_int internal calcium concentration
Na_ext external calcium concentration
Vm membrane potential
Vnaca reveral potential of ncx
naterm Na_ext^stoic, used for Jafri formula
caterm Ca_ext ^hill, used for Gall formula
chi F/RT
Kmca affinity for calcium
Kmna affinity for sodium
kmhill km^hill
naicao nai^hill*cao
gamma partition coefficient
T temperature in Kelvin
I current
Gbar maximal conductance
Gcurrent conductance for compartment
ksat another constant used by jafri
Vunits units of membrane potential
valence calcium charge
hill hill coefficient
stoich stoichiometry of pump (how many sodium for calcium)
Na_msg whether sodium conc messages are being passed
ncxtype whether using Gall (0) or Jafri (1) formula
DESCRIPTION
Sodium calcium exchanger equations.
if ncxtype = 0 uses Gall formula:
I = K * Cai^Hill/(Cai^Hill + Kmca^H) * (Vm - Vnaca) where
Vnaca = RT/F(stoic*ln(Nao/Nai) - ln(Cao/Cai))
if ncxtype = 1 uses jafri formula:
I = K* (Cao*Nai^stoich*exp(gamma*FV/RT) - Cai*Nao^stoich*exp((1-gamma*FV/RT))
divided by
(Kmna^stoich+nao^stoich)*(Kmca+cao)*(1+ksat*exp(1-gamma)FV/RT))
if Na_msg = 0 then Na concentrations are initialized, no Na messages required. if Na_msg = 1, then Na messages are required. In all cases input messages of calcium are required. The calcium and sodium input message in concentration units.
Requires Vm message, units indicated with Vunit field addmsg from ncx to rxnpool CURRENT valence current.
Object Type: reaction datatype react_type function reaction() class [ segment ] author A. Blackwell ERIM Aug 96 ; revised GMU Dec 99
VALID ACTIONS
SET RESET PROCESS INIT
VALID MESSAGES
[1] PRODUCT conc /* concentration or quantity of products */
[0] SUBSTRATE conc /* concentration or quantity of substrates */
FIELDS
kb backward rate constant
kf forward rate constant
kbprod kb * products
kfsubs kf * substrates
DESCRIPTION
An element to compute kf*substrates and kb*products for nth order reactions. dC/dt = kf * substrate * substrate * ... - kb*product* ...
For each substrate and product in reaction, a message must be received (n times, if n moles required). Input and rate constants both must be in units of concentration, (use RXN2 to send message to rxnpool) or both must be in units of moles (use RXN2MOLE).
addmsg from reaction to substrate rxnpool RXN2 (or RXN2MOLES) kbprod kfsubs addmsg from reaction to product rxnpool RXN2 (or RXN2MOLES) kfsubs kbprod
Object Type: rhodopsin datatype rhodopsin_type function rhodopsin() class [ segment ] size 7128 bytes author A. Blackwell GMU March 02
VALID ACTIONS
CHECK SET RESET PROCESS INIT
VALID MESSAGES
[1] INACT inactivation
[0] ISOM isomerization
FIELDS
input_slice
slice
isom
last_isom
villus
total_villi
slice_villi
villi_isom
isom_time
total_time
active_villi
villus_vol
villus_xarea
villus_sa
slice_vol
slice_xarea
slice_sa
factor
total_isom
depletion
effective
villi_list
inact_const
inact_rate
inact
last_inact
total_inact
units
conc
quantity
len
radius
DESCRIPTION
Quite a complicated object for calculating stochastic activation of rhodopsin molecules and includes stochastic inactivation by Rhodopsin Kinase or Arrestin. It keeps track of:
Number of rhodopsin molecules per villi, which allows decrease effectiveness with additional villi
time of rhodopsin activation, which allows decrease effectiveness over time due to depletion
Object Type: rxnpool datatype rxnpool_type function rxnpool() class [ concentration ] [ segment ] size 280 bytes author A. Blackwell ERIM Aug 96; revised GMU Dec 99; GMU Mar 02
VALID ACTIONS
RESTORE2 SAVE2 CHECK RESET PROCESS INIT
VALID MESSAGES
[6] VOLUME vol SAin SAout //This input will change the volume and surface area of the compartment
[5] RXN0MOLES A //The input value causes quantity independent increase in molecules
[4] CURRENT charge current //Two input values - the current, and the valence of the ion flowing
[3] RXN2MOLES A B //Two input values provided from reactions between elements that track quantity
[2] RXN2 A B //The input value is a rate constant, multiplied by the existing molecule conc or quantity
[1] RXN1 B //The input value is a rate constant, multiplied by the existing molecule conc or quantity
[0] RXN0 A //The input value causes concentration independent increase in molecules
FIELDS
Conc concentration
quantity quantity in molecules
previous_state
Cmin minimum concentration
Cinit initial concentration
Qinit initial quantity in molecules
len length of cylindrical pool
radius radius of cylindrical or spherical pool
vol volume of pool
SAside side surface area of cylinder
SAout outer surface area of spherical shell
SAin inner surface area of spherical shell
type whether pool integrates concentration (0) or quantity (1)
units 1 for moles, 1e-3 for mmoles, 1e-6 for umoles
Iunits 1e-12 to convert from nA, msec to A,sec
Dunits 1 for meters, 1e-4 for cm, etc
VolUnitConv Dunits^3, converts volume to SI units
DESCRIPTION
Rxnpool is an object used to keep track of molecule concentration and quantity; thus it interacts with reactions, diffusion, pumps,current, and calcium release objects. Regardless of the source of the molecules, it accumulates fluxes into variables A (rate of change independent of concentration) and B (rate of change proportional to concentration) and solves d[C]/dt = A - B*[C].
Inputs of concentration for 0th, 1st and 2nd order reactions are provided through the messages RXN0, RXN1 and RXN2. Inputs of Moles are provided through the messages RXN0MOLES or RXN2MOLES. Inputs of current (uses physiologists convention - that means a negative current is inward, e.g. a negative calcium current increases calcium concentration. To provide input from tabchannels which use modelers conventation, provide a charge (valence) of -2 for calcium (instead of +2). To provide input from either diffusion, CICRflux, an enzyme reaction or a pump, use RXN0MOLES, because these calculate flux between compartments (rxnpools) with unequal volume. Thus, the change in concentration is different for the two different compartments
rxnpool and all other chemesis objects allow for any consistent set of units. Iunits is a value that specifies which units are used, thus if currents are in units of nanoAmps, then Iunits should be 1e-9. If current is in nA and the clocks units are msec, then Iunits = 1e-12
Dunits indicates the units used for length (needed for diffusion). units is a value that specifies which units for quantity (e.g. moles, mmoles, etc) are used. type indicates whether to do the calculations in units of concentation or quantity. If type = 0, converts molecule inputs to concentration and then integrates; if type = 1, converts concentration inputs to molecules and then integrates.
Object Type: wgtavg datatype wgtavg_type function wgtavg() class [ segment ] size 168 bytes author A. Blackwell GMU Oct 2011
VALID ACTIONS
RESET PROCESS INIT
VALID MESSAGES
[0] ValueWgt Value wgt
FIELDS
totValue total weighted value"
totwgt total of weights
meanValue weighted mean
DESCRIPTION
An object to calculate a weighted average. Divides total weighted
value by total weights. Can calculate the mean calcium from unequal
size calcium shells by using volume as weight.
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