Asunto relevante: cambios en concentración, en posición y tiempo

creación y destrucción de moléculas/células

40 kg/día de ATP, por ejemplo …
La dinámica del citoesqueleto: crecimiento y destrucción
La velocidad de polimerización es importante para migración.

0.2µ/s
… de toda la célula y de parásitos intracelulares también.

0.05 – 1.4 µ/s

para 0.2 µ/s

actina: 3 nm

à 70 mon/s
La velocidad de polimerización depende de la concentración:
necesito saber cuánta hay, y dónde

quiero saber dónde y cuándo hay qué, y cómo evoluciona

caso más sencillo: distribución homogénea
 El caso más sencillo: decaimiento

tratamiento para poblaciones, con valores promedio

 time distribución
Análisis microscópico: of one second
de or one minute
tiempo or one
de espera paraweek. Howeve
que decaiga
consider a huge collection of such molecules, it makes sen
of an average lifetime associated with these molecules,
what the decay constant captures.
We can use this trajectory picture with our “trajectories-a
approach introduced in Figure 13.14 (p. 520). We discretiz
N intervals of el
ti es length
tiempo (soespera
"t de the total time
de la t = N"t) iand th
trayectoria
probability of a given trajectory by multiplying the prob
what happens at each time es el step over
tiempo dethe entire
vida trajectory
promedio
ple, if the molecule survives for N time steps and dec
(N + 1)th time
¿cuálstep,
es lathen the probability
probabilidad de queofdecaiga
that process
en t? is
p(t)"t = (1 − k"t) × (1 − k"t) × · · · × (1 − k"t) ×k"t,
N time steps

es la probabilidad de que decaiga en un paso

where k"t is the probability of a decay during any tim
1 − k"t is the probability of no decay at a given time
function p(t) is a probability density and requires that w
p(t)"t to compute the probability that the decay occurs be
t and t + "t. If we use the fact that "t = t/N, this re
rewritten as
que es lo mismo que ! "N
kt
Cuando algo decae, se convierte en otra cosa, no desaparece.

y si es reversible

conservación de masa
 Siguiente nivel de complicación: reacciones bimoleculares

ahora A y B deben estar en el mismo

sitio al mismo tiempo

the number of ligand–receptor complexes due to binding of ligand to

receptor can be written as
⎛ ⎞
⎜ NL NR ⎟
⎜ ′ ⎟
!NLR = −(koff !t)NLR + ⎜ " × ×(kon !t)⎟ ,
⎝ " " ⎠
decay term no. of boxes box occupancy prob.

los que se rompen + los que se forman (15.30)

cular,
= −kwe
off have + v kon , (15.31)
"v "v "v "v
' ( ' (
onddterm NLR
on the right
= −koff we +
" NL N
NLRhave divided R 2multi-
and ′
v kon , (
dt "v
in order to convert to concentration
"v "v "vvariables
"v such
] = NR /"v, and [LR] = NLR /"v. These manipulations
n para
on theponerlo
15.30second term on
into en términos the right we have divided and
de concentraciones,
y v twice in order to convert to concentration variables
d[LR] [R] = N /"v, and [LR] = N /"v. These manipul
NL /"v, = −koff [LR]
R + kon [L][R], LR (15.32)
dt
rm Equation 15.30 into
ecular on-rate
al equilibrio is no
[LR] related
cambia:to the lattice model rate
vkon d[LR]
′ , and has units of =
M−1 s −1 . This heuristic deriva-
−koff [LR] + kon [L][R], (
o link simple latticedt models with macroscopic rate
in terms of concentration variables.
the bimolecular on-rate is related to the lattice mode
nt by kon = vkon
′ , and has units of M−1 s−1 . This heuristic d
tants Have a Dynamical Interpretation in Terms of
ows how to link simple lattice models with macroscopi
ns defined in terms of concentration variables.
formalism described above provides a useful oppor-
ntact with
rium what weHave
Constants already
a know about the
Dynamical equilibria
Interpretation in Ter
states.
at the ability. We adopt a strategy in which time is discretized in
ous in length "t
La dinámica deand, at eachiónicos:
los canales time step, the
k
sistema+ channel
de dos can undergo a
estados
ent in O ! C,
from its current state or it can remain k− in the same state. The
icons conexión
of interest is of the form entre un comportamiento microscópico
ed states. binario y un comportamiento macroscópico
where O signifies the open state, kC+
signifies the closed st
and k− are the rate analógico
constants O ! C,
that determine the proba
k−
change of state during a given time step. The change in the
open channels
where in a quiero
O signifies given la
the open
probabilidad
time step C
state, can de
be estar abierto
written
signifies as
the closed st
and k− are the rate constants that determine the proba
change of state during "NaOgiven NO "t
= −k+time + k−The
step. NC "t .
change in the
open channels in a given time O→C step can beC→O written as

If we divide both sides "N

by O"t, we+find
= −k NO "tthe
+ krate of .change in
− NC "t
mbrane of open channels as O→C C→O

If we divide both sides "N O we find the rate of change in t

by "t,
= −k+ NO + k− NC ,
membrane of open channels as "t
which can be further simplified
"NO by dividing this equation
and using pO = NO /N and pC
==
−kN+CN O+k
/N. −N
If C , examine th
we
"t
"t → 0, this results in the differential equation
which can be further simplified by dividing this equation
and using pO = NO /N dp and
O pC = NC /N. If we examine th
 partiendo de todos los canales abiertos (pO(0) = 1)

obtengo pO(t) de registros de actividad del canal

haciendo un histograma de tiempos de espera

obtengo la vida media del estado abierto
(o cerrado, dependiendo del histograma hecho)
 Equilibrios rápidos: una cadena de reacciones

definiendo

≈1
<< 1
y dividiendo
entre k- à

como la tercera ecuación está desacoplada de las otras dos,

lento rápido
para

k=1
ε = 0.01
A(0) = 1
 Michaelis-Menten y la cinética enzimática

solución numérica para

Análisis de estado estacionario
Suponiendo que

definiendo

liga entre concentraciones y velocidades

El citoesqueleto en eterna creación y destrucción
Lo complicado es empezar.
Las bacterias tienen homólogos de actina y tubulina.

ParR en gris
Modelos de polimerización de actina

busco

Pn(t): probabilidad de tener un

polímero de longitud n en el
tiempo t

<L>: longitud promedio de los

polímeros
 El modelo más complejo

concentración (µM)

crece mucho más rápido en el extremo barbado

 Análisis al equilibrio

concentración crítica c*

si à función decreciente
 Fluctuaciones en el tamaño de los polímeros
¿Cuánto tiempo hay que esperar para que se dé una de 1µ? ~9 horas
demasiado lento …

P(a)

P(-a)

al equilibrio P(a) = P(-a)

n one time step is

⟨x⟩ = aP(a) − aP(−a) = 0. (15.81)

in !t
 . Since our rate equation picture does not consider fluctua-
Visión cinética del problema de polimerización
we note that the dynamical equation describing the number of
ers, n, in eachafilament
crecimiento partir deisMidentical
semillasfor(noeachhayfilament and is
lag phase)
y concentración instantánea
! "
dn Mn(t)
= kon c0 − − k , (15.88)
dt V off

growth shrinkage

0 is the initial concentration of monomers in the volume V and

e number of nuclei that seed the growth. This equation says
ere will be an addition of monomers with rate kon , which is pro-
al to the monomer concentration. In addition to the growth,
also the potential of shrinkage
a es of the
el tamaño delfilaments
monómero as a result of
term. As the monomer concentration varies, there is a competi-
ween these two terms. The significance of the factor c0 − Mn/V
it captures the instantaneous concentration.
a tiempos más cortos queOur picture is of
éste
f fixed volume V that has some initial number of monomers
el comportamiento es lineal
ilable for polymerization. As the filament growth process pro-
he number of available monomers is reduced since ever more
ers are now tied up in filaments (the number of monomers in
ments is Mn) and aremuy
a tiempos hence unavailable
largos se saturafor further polymeri-
Note that in this simple model, the total number of nuclei, M,
.
olution to this dynamical equation is found by noting that we
Our goal is to write a rate equation for the dynamics of this reaction.
La evolución
However, the equations temporal
are coupled. dethe
That is, Pn(t)
equation for the evo-
lution of Pn depends upon the evolution of both Pn−1 and Pn+1 . To find
the time evolution of Pn , we have to consider the “adjacent” reaction
given by

se añade o se pierde un monómero

kon
Pn−1 + P1 ! Pn , (15.99)
koff

which will account for the “decay” of a polymer of length n into

one of length n − 1. The time evolution of the probability distribu-
tion is governed by four distinct classes of process and is captured
mathematically as

dPn
= kon Pn−1 P1 + koff Pn+1 − kon Pn P1 − koff Pn .
dt
addition to Pn−1 removal from Pn+1 addition to Pn removal from Pn

(15.100)

One question of immediate interest that emerges from a model of this

kind is: what is the average length of a polymer as a function of time
whose growth is described by Equation 15.100? If a is the length of a
monomer, we can write the total average length of the filament as
Siguiente nivel de complicación: cada punta tiene velocidades diferentes
el cociente de constantes de velocidad
de una punta es igual al de la otra:
misma interfaz de interacción

arriba de c* todos crecen …

así no son los microfilamentos,
pero sí la flagelina
 Las dos puntas no son iguales: hidrólisis de nucleótidos.
en una se reclutan y pierden actina-ATP; en la otra, actina-ADP
este modelo ya presenta “treadmilling”:
lo que crece en una punta lo pierde en la otra

parece que camina el filamento

 available monomers. Recall that our picture is that th
time 89 s Inestabilidad the filament
dinámica: has a velocity
catástrofes vtip and that the hydrolysi
y rescates
2 mm rate 1/τ . Within this model, the critical condition for
that the velocity of the hydrolysis front equals that o
igure 15.33: Microtubule and is given by condición crítica:
readmilling. Individual microtubules
ave been observed to undergo
readmilling inside living cells. The dxtip a
uorescently labeled microtubule looks = .
dt τ
s though it is sliding from left to right.
However, as indicated by the middle growth rate of leading edge speed of hydrolysis front
rrow, which points to a fixed point
within the microtubule, in fact one end
he minus end, on the left) is
crece
This equation mientras
says añada
that in the timemonómeros
it takes for the n
hortening and the other (the plus end, be added más
to therápido
growing
quetip,lathe monomerde
hidrólisis at ATP
the tip
n the right) is elongating. (Adapted hydrolyze its nucleotide triphosphate, where we hav
rom C. M. Waterman-Storer and plifying assumption that the cap is only one monom
. D. Salmon, J. Cell Biol. 139:417,
997.)
critical condition written mathematically above really
since it is only when the hydrolysis front is moving
sólo este hidroliza
growing tip that we are guaranteed that the front w
the tip and induce a catastrophe.
The physical picture of the catastrophe, then, is
trophe starts once the hydrolysis front catches th
because at that point the GTP (or ATP) growth rates
by their GDP (or ADP) counterparts. Said differently,
inates for the GDP monomers, whereas the on rate d
GTP monomers. This model predicts a very specific
the catastrophe rate on the concentration of monom
la velocidad de polimerización
depende de la concentración de
monómeros

condición crítica:

tiempo entre catástrofes:

suponiendo que se añaden más rápido de lo que se caen

 tasa de catástrofes (1/tcrit)
en función de c0

tasa de catástrofes (1/tcrit) en

función de la velocidad de
crecimiento

supone hidrólisis en cualquier

lado, y que pueden haber
fluctuaciones de tamaño