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Contractile Mechanisms 2 - Huxley

1957 Model


J. Jeremy Rice
IBM T.J. Watson Research Center, P.O. Box 218,
Yorktown Heights, NY 10598
johnrice@us.ibm.com
914-945-3728


Last slides from last lecture
Solved problem from McMahon, p. 21
Solved problem from McMahon
Solved problem from McMahon
(Assumes not less than slack length)
the derivative of
^

Solved problem from McMahon
Exponential fall
has terms with
exp(-(t-t
init
)/t)
where t = B/K
Exponential rise
has terms with
(1-exp(-(t-t
init
)/t))
where t = B/K
Method 2
0 at t 0 T
init init
= =
T
0

0
t = 0 C C +A
2C +A t -> infinity
Assume output of active element is T
0
for infinitely long time
) e 1 ( T ) C ( T
C
B
K
0

=
0
T T =

t t / ) t t (
init
/ ) t t (
init init
e T ) e 1 ( T ) t ( T

+ =
where t = B/K

Therefore and ) e 1 ( T ) t ( T
t
B
K
0

=
Method 2
T
0

0
t = 0 C C +A
2C +A t -> infinity
) A (
B
K
e ) C ( T ) A C ( T

= +
t t / ) t t (
init
/ ) t t (
init init
e T ) e 1 ( T ) t ( T

+ = where t = B/K

Therefore
C at t ) C ( T T
init init
= =
Now repeat process but move forward in time so t
init
= C
0 T =

and
Assume output of active element is 0 for infinitely long
) C ( T
t / ) C t (
e ) C ( T ) t ( T

=
and
) A C ( T +
Note that time constant will change if
more elastic elements are added

For example, if K
PE
and K
SE
are above slack length and
total length x is fixed, then t = B/(K
PE
+ K
SE
)
Warning: K
PE
and K
SE
are nonlinear elements
Answer to part b
= 1 when C (A can be anything)

t = 0 C C +A
2C +A
T
0

0
t = 0 C C +A
2C +A
= 1 when A (C can be anything)

t = 0 C
C +A 2C +A
= 2 when A and C 0


T
0

0
T
0

0
x =(1+e
K( A+C)/B
)
= 2 when C 0 and A 0
Goals
Force-Velocity relations
Evidence for sliding filament theory
Derivation of Huxley '57 Model


Force-Velocity Relations
Experimental setup
Force-velocity relations
Force-velocity relations
Simple models fail to
explain the downward
droop in force-velocity
relations
Except for extreme cases maximum
shortening velocity is constant (V
o
)
Factors affecting the measurement of V
o
.

A) time of release. V
o
(open circles) is independent of
time when twitch force (solid line) is >70% of F
0
.

B) sarcomere length on F
o
. Active and passive
force development as function of sarcomere length

C) sarcomere length on V
o
. Sarcomere length does
not affect V
o
above slack length (~1.90 m).

D) speed of release. Increasing the rate of muscle
release does not affect sarcomere shortening velocity
over a wide range. This demonstrates that the actual
maximal shortening velocity of the sarcomeres is rate
limiting, and thus allows for the direct measurement of
V
o
.
* Do not worry about length and activation state just think of
action of crossbridges as setting force-velocity relationship
More XB are attached as
velocity decreases
* But this is just part of the story - extension changes also
Peak power occurs midway in
F-V relations
Evidence for sliding
filament theory
What was "known" - evidence for
sliding filaments and cycling force
generators
The smallest contractile unit is the sarcomere
The sarcomere is composed of actin & myosin
Filaments slide but do not change length
Force proportional to degree of overlap
The maximum sarcomere length for contractile force
development is ~3.6 m - above this length no active force
is generated
Maximum unloaded velocity is independent of SL

Except for extreme cases maximum
shortening velocity is constant (V
o
)
Factors affecting the measurement of V
o
.

A) time of release. V
o
(open circles) is independent of
time when twitch force (solid line) is >70% of F
0
.

B) sarcomere length on F
o
. Active and passive
force development as function of sarcomere length

C) sarcomere length on V
o
. Sarcomere length does
not affect V
o
above slack length (~1.90 m).

D) speed of release. Increasing the rate of muscle
release does not affect sarcomere shortening velocity
over a wide range. This demonstrates that the actual
maximal shortening velocity of the sarcomeres is rate
limiting, and thus allows for the direct measurement of
V
o
.
* Do not worry about length and activation state just think of
action of crossbridges as setting force-velocity relationship
Alternative theory proposed opposite
charges exist in thick and thin filament
Contraction from electrostatic attraction
Hard to reconcile with maximum velocity being
independent of sarcomere length
Derivation of Huxley '57
Model
Review three key concepts from basic probability:
1. Probability Density Functions
Example:
Consider an electron of a hydrogen atom. One could
draw an approximate probability density function (p.d.f.)
for its location in terms of distance from the nucleus = r.
Let h(r) be the function below that defines this p.d.f.
r
proton
r=0 r
h(r)
electron
The way to interpret a p.d.f. is that a probability can be
computed as an area under the curve. For example
the probability of the electron being closer than r
0
is
computed as:
{ } dr r h r r
r
}
= <
0
0
0
) ( Pr
r=0 r
h(r)
r
0
r
1
Likewise, the probability of the electron being between r
0
and
r
1
is computed as:
{ } dr r h r r r
r
r
}
= < <
1
0
) ( Pr
1 0
By definition, the p.d.f. does not directly report the probability
of finding an electron at a given fixed distance, r
0
:
{ } ) ( Pr
0
r h r r = =
In fact, the probability for any given distance, r
0
, is 0.
See that:
{ } 0 ) ( Pr
0
0
0
= = =
}
dr r h r r
r
r
A probability is always between 0 and 1 so if we
assume the electron is always found at some distance
from the nucleus then:
More formally, we define the the p.d.f. as a limit:
{ }
(
(
(

A
=
(

A
A + < <
=
}
A +
A A
u
dr r h
u
u u r u
u h
u u
u
u u
) (
lim
Pr
lim ) (
0 0
{ } 1 ) ( 0 Pr
0
= = < <
}

dr r h r
General rule: The summation of p.d.f. over all possible values
must be = 1.
We define a conditional probability as probability of an
event A given that an event B has occurred. This is
written as:
{ } { } { } B B A B A Pr Pr & Pr =
{ }
{ }
{ } B
B A
B A
Pr
& Pr
Pr =
This relation may make more intuitive sense when
rearranged as:
2. Conditional Probability

One can also rearrange relationship to this:
{ } { } { } B A B A B Pr / & Pr Pr =
{ } { } { } B B A B A Pr Pr & Pr =
Note: this is only true if A and B are independent
{ } { } { } B A B A Pr Pr & Pr =
{ } 1 . 0 2 SBE & 1 SBE Pr =

Consider that probability that a given student at JHU takes
both SBE 1 and SBE 2 is 0.10 (1 out 10 students take
both), or:
We can compute the probability of a student taking SB1 as:
For more examples, see tutorials on the internet, such as:
http://www.mathgoodies.com/lessons/vol6/conditional.html

Now consider the probability that a student takes SBE 2
given that the student has taken SBE 1 is 0.9 (9 out 10
students SBE 2 after taking SBE 1), or

{ } 9 . 0 1 SBE | 2 SBE Pr =
{ } { } { } 111 . 0 1 SBE | 2 SBE Pr / 2 SBE & 1 SBE Pr 1 SBE Pr = =
Random Rate Theory
Try to decrease your odds of rolling a 1 on a six-
side die by first rolling a 1 and then taking the
next roll for real.
Reasoning: Odds of rolling two 1s on two
consecutive dice is 1:36. This is low so you are
likely to have a roll higher than 1.
Odds of rolling two 1's on two dice is 1:36, but
conditional probability of rolling a 1 second time
after rolling the first 1 is 1:6 (as you might
expect).

{ } { } { } B B A B A Pr Pr & Pr =
Random Rate Theory
{ }= 1 by followed 1 Rolling Pr
Faulting reasoning: Odds of rolling two 1 on two
dice is 1:36, but conditional probability of rolling
a second 1 after rolling the first 1 is 1:6 (as you
might expect).
{ } { } { } B B A B A Pr Pr & Pr =
{ } { }
36
1
6
1
6
1
1 first the Rolling Pr 1 first the Rolling 1 by followed 1 Rolling Pr
= =

3) State variables represent probabilities of random events


Consider a random process like a channel opening
and closing. State at any given moment tells you
little about long-term behavior,
From cellsalive.com
When considering a random process like a channel
opening and closing, each channel looks like this:
C
O
f
g
For this channel, if we assume f = 1 s
-1
and g = 2 s
-1
, then
steady-state probability of the channel being open is
computed as:
{ }
3
1
Pr =
+
= =
g f
f
open channel
Of course, this does not mean the channel is 1/3 open
because only states "closed" and "open" exist.
However, if we were to average a large number of
channel responses together, we would get something
like this:


Sample many
runs and
average to get
better estimate
of probability.
}
.
.
.
0
1
.
.
Run 1
Run 2
Run n
.
0
1
1/3
time
So instead of tracking a each channel, we can define a
state variable based system to capture the behavior of
the whole population. When implemented this way,
average behavior can calculated without averaging (and
associated noise and computational cost).
C
O
f
g
{ }
3
1
Pr =
+
= = =
g f
f
open channel O state of Value
{ }
3
2
Pr =
+
= = =
g f
g
closed channel C state of Value
Derivation of Huxley 57 Model
Assumptions:
1. Contractile machinery only
2. Plateau region of length-tension
3. Muscle fully activated
4. Constant velocity (parameter in model)
5. Crossbridges (XBs) always completes full cycle to
detach and uses 1 ATP in the process
6. Single myosin near every A site and interaction
between this pair is independent of all other pairs of A
sites and myosins


Setup for Huxley '57 model
X

We consider model on right to be equivalent to model on left.
Model is built around actin binding sites called A sites on thin
filament. Myosin heads from thick filament can bind to one
and only one nearby A site.
A site
equilibrium
myosin position
Thick filament
Thin filament
A site
X

EM micrographs shows evidence of
crossbridges but no real detail
Setup for Huxley '57 model
X
1
< 0
Forces are only considered in left-right directions parallel to
thick and thin filaments. When an A site is bound to myosin,
force is generated with respect to the distortion of myosin from
its equilibrium position. When A site is bound exactly at the
equilibrium position (i.e. X
3
), no force is generated.
equilibrium
myosin positions
X
2
> 0
X
3
= 0
A site 1
A site 2 A site 3
Setup for Huxley '57 model
X
1
< 0
When an A site is bound to myosin, force is generated with
respect to the distortion of myosin from its equilibrium position.
Linkage is assumed to be a simple spring so that T = kX. For
each A site with myosin bound, T = kX. Therefore, T
1
< T
3
=0 <
T
2
.
A site 1
equilibrium
myosin positions
X
2
> 0
X
3
= 0
A site 2 A site 3
k
k
k
Setup for Huxley '57 model
Distance between A sites = l
Diagram shows distance between A sites and equilibrium myosin
positions. A whole population of A sites is assumed to sample equally all
X values because A sites and equilibrium myosin positions are unequally
spaced. If l is distance between A sites and m is distance between
equilibrium myosin sites then il jm for any small integer i and small
integer j.
A sites
equilibrium
myosin positions
Distance between equilibrium myosin sites = m
Position of myosin heads on
thick filament
Pairs of heads emanate 180
degree apart in radial direction at
each step
Radial direction of heads rotate
~60 degrees at next step in axial
direction (distance = ~14.3 nm)
a "pseudo-repeat" happens on
the 3th steps as heads will be
emanate in same radial direction
(distance = ~43 nm)
a
x
i
a
l

d
i
r
e
c
t
i
o
n

radial direction
Thin filament is a two-stranded helix of
actin monomers
From http://www.kent.ac.uk/bio/geeves/Research/home.htm
"Pseudo-repeat" = 13 units
5.54 nm
2.77 nm
"Pseudo-repeat"
37 nm
True repeat = 26 units
Setup for Huxley '57 model
Distance between A sites = l (small L)
X
1 X
2
X
3
X
4
Model assumes distance l between A sites is large and
interactions are with only one nearby myosin. Hence, each
myosin can interact with only one A site at a time. Therefore,
the cases shown above (for X
2
and X
3
) cannot happen.
A sites
equilibrium
myosin positions
Setup for Huxley '57 model
X
1

The thick and thin filaments slide past each other at a constant
velocity V. We assume that the motion results from combined
action of many force generators acting across the whole muscle,
so the sliding velocity is not affected by the local attachment or
detachment events. Note: velocity is a parameter in the model.
equilibrium
myosin positions
X
2

X
3

Sliding in V > 0 direction
(if thick filament fixed)

Sliding in V < 0 direction
(if thick filament fixed)
Setup for Huxley '57 model
X
1

As thick and thin filaments slide past each other at a constant
velocity V, the relative position of A sites compared to
equilibrium myosin positions changes. Therefore, when V>0,
X
1
, X
2
and X
3
all get smaller (less positive or more negative)
with time.
equilibrium
myosin positions
X
2

X
3

Sliding in V > 0 direction
(if thick filament fixed)

Sliding in V < 0 direction
(if thick filament fixed)
g

4

0

x

f
1
XB attach only in this range
XB can detach at any distortion
Attachment rates as function of X
5

3

2

1

g
2
g
1
h

g

f

Attachment rates as function of X
X

< 0
Attachment rate between A site and myosin
are a function of the relative distance
between the A site and equilibrium myosin
position. In the model, f(X) is the function
defined to control attachment. Function f(X)
increases linearly from X=0 to X=h.
X

= h/2
X

= 0
f(X)
g
4
0
x
5
3
2
1
h
g
f
g
4
0
x
5
3
2
1
h
g
f
g
4
0
x
5
3
2
1
h
g
f
g
4
0
x
5
3
2
1
h
g
f
Detachment rates as function of X
X
1
< 0
In the model, g(X) is the function defined to
control detachment as a function of the relative
distance between the A site and equilibrium
myosin position. In the positive range, g(X)
increases linearly from X=0. In the negative
range, g(X) is large so that the negative
distortion XBs ("draggers") detach quickly.
X

> h
X

= 0
g(X)
Let n(x,t) be a conditional probability describing the
likelihood that an XB is attached given that the A site is
at displacement x from the nearest XB equilibrium
position.
To be more rigorous:
Conditional probability vertical
bar means given that
(
(
(

A +
=
A
x x to x
range in A
attached XB
has site A
Pr lim ) t , x ( n
x 0
Note that a more intuitive function describes when an A
site is attached and the A site is between x and x + Ax
We can use rule from basic probability
(
(
(

|
|
|
.
|

\
|
A +
|
|
|
.
|

\
|
A
=
A
x x to x
range in A
&
attached XB
has site A
Pr
x
lim ) t , x ( n

x
1
0
{ } { } { } B B A B A Pr Pr & Pr =
(
(
(

A +

A + A
=
A
x x to x
range in A
x x to x
range in A
attached XB
has site A
x
t x n
x
Pr Pr
1
lim ) , (
0
(
(
(

A + A
-
(
(
(

A +
=
A A
x x to x
range in A
x x x to x
range in A
attached XB
has site A
t x n
x x
Pr
1
lim Pr lim ) , (
0 0
Make a substitution for probability inside limit
Substitute limit above with product of limits below
) , (

) , ( ) , (

t x h t x n t x n - =
Probability Density
Function
Conditional
Probability
) , (

) , ( ) , (

t x h t x n t x n - =
is a probability density function describing the
positions of A sites with respect to equilibrium
XB positions
Model assumes is constant over all possible x
values between -l/2 and l/2 as shown below:
l/2
-l/2
1/l
x
h

Setup for Huxley '57 model


Distance between A sites = l
Diagram shows distance between A sites and equilibrium myosin
positions. A whole population of A sites is assumed to sample equally all
X values because A sites and equilibrium myosin positions are unequally
spaced. If l is distance between A sites and m is distance between
equilibrium myosin sites then il jm for any small integer i and small
integer j.
A sites
equilibrium
myosin positions
Distance between equilibrium myosin sites = m
Therefore, h = constant.
>

Continue with derivation
For steady-state response:
Apply chain rule:
We know that:
0 =
c
c
+
c
c
dt
dt
t
n
dt
dx
x
n
( )
0
,
=
dt
t x dn
1 =
dt
dt
v
dt
dx
=
Rearrange to get:
0 =
c
c
+
c
c
t
n
v
x
n
t
n
x
n
v
c
c
=
c
c

( )
( ) ( ) | | ( ) ( ) x n x g x n x f
t
x n
=
c
c
1
( )
( ) ( ) t x n x n
dt
t x dn
,
0
,
of instead use
where state steady Consider

=
Unattached A site fraction Attached A site fraction
site A from detachment of rate
- site A to attachment of rate =
c
c
t
n
( ) ( ) | | ( ) ( ) t x n x g t x n x f , , 1 =
Combine above results:
Can find solution for specific
cases if we define f(x) and g(x)
with units of s
-1
( ) ( )
t
x n
x
x n
v
c
c
=
c
c

( )
( ) ( ) | | ( ) ( ) x n x g x n x f
x
x n
v =
c
c
1
( ) ( )
2
; 0 : 0 g x g x f x = = <
( ) ( )
h
x g
x g
h
x f
x f h x
1 1
; : 0 = = s <
( ) ( )
h
x g
x g x f h x
1
; 0 : = = >
g
4
0
x
f
1
5
3
2
1
g
2
g
1
h
g
f
n g
dx
dn
v
2
=
} }
= dx
v
g
n
dn
2
Apply constraint that if then solution is continuous
at x=0 and x=h. One can write:
Now solve for three region assuming V > 0:
Region 1 -
) ( ) (
) 0 ( ) 0 (
+
+
=
=
h n h n
n n
0 = V
( ) ( )
2
; 0 : 0 g x g x f x = = <
( )
0
,
= =
c
c
dt
t x dn
dx
dn
x
n
where state steady in
Integrate to get:
v
x g
e C x n
2
1
) ( =
T.B.D. constant a is ) ( where
C
o
e C
1
=
xn
h
g
n x
h
f
dx
dn
v
1 1
) 1 ( =
( ) ( )
h
x g
x g
h
x f
x f h x
1 1
; : 0 = = s < Region 2 -
0
2
ln C x
v
g
n + =
xn g n x f
dx
dn
vh
1 1
) 1 ( =
xn g f x f ) (
1 1 1
+ =
) )( (
1 1
1
1 1
n
g f
f
g f x
+
+ =
Rearrange to get:
xdx
vh
g f
g f
f
n
dn
1 1
1 1
1
) (
+
=
+
+
Integrate to get:
2
2
1 1
1 1
1
2
) ln( C
x
vh
g f
g f
f
n +
+
=
+
+
)
`

+
+
=
+
+
2
2
1 1
1 1
1
2
exp C
x
vh
g f
g f
f
n

2
exp
2
1 1
3
1 1
1
)
`

+
=
x
vh
g f
C
g f
f
n
2
3
where
C
e C =
( ) ( )
h
x g
x g x f h x
1
; 0 : = = >
Region 3 -
If we assume shortening then no crossbridges can be
attached at x>h. This is equivalent to n(x,t)=0 for x>h.
Now determine the constants using the continuity
conditions:
) ( ) (
+
= h n h n

2
exp 0
2
1 1
3
1 1
1
)
`

+
=
x
vh
g f
C
g f
f
)
2
2
1 1
1 1
1
3
h
vh
g f
exp(
g f
f
C
+

+
=
Substitute constant back into original equation:
) 0 ( ) 0 (
+
= n n
h x e
g f
f
x n
x h
vh
g f
< <
(

+
=
+

0 for 1 ) (
) - (
2
1 1
1
2 2 1 1
Find C
1
using the other continuity condition:
1
0
1
2
0 C e C n
v
g
= =
-

) ( (

+
=
+

+
2 1 1
2
1 1
1
1 ) 0 (
h
vh
g f
e
g f
f
n
(

+
=
+

2 1 1
2
1 1
1
1
1
h
vh
g f
e
g f
f
C
Substitute constant back into original equation:
Define
where S is a full sarcomere length (~ 2 m), S/2 is a half
sarcomere length, and V is normalized velocity in half
sarcomere lengths per second.
0 1 ) (
2 2 1 1
2
1 1
1
<
(

+
=

+

x e e
g f
f
x n
v
x g
h
vh
g f
for
Make a change of variables:
V
S
v
2
=
) (
1 1
g f
S
h
+ = |
and
The three regions can now be defined as:
Must define rates for XB cycling. Can use the ratios
below:
( ) 0 = > x n h x :

SV
x g
V
e e
g f
f
x n x
2
1 ) ( : 0
1 1
1
(

+
= <

|

)
(
(

+
= < <

V
h
x
e
g f
f
x n h x
|
1 (
1 1
1
2
2
1 ) ( : 0
The following plots on following slides are the result.
16
3
1 1
1
=
+ g f
g
919 . 3
1 1
2
=
+ g f
g
Results for Huxley '57 model
In isometric conditions (V=0), for given distances between X=0
and X=h, there is a high probability of attachment of the A sites to
the myosin. Attached XBs with positive distortion are "pullers".
X

< 0 X

= h
-
X

= h/2
(a)
(c)
(b)
(a)
(b)
(c)
n(h/2) = 0.8
n(h
-
) = 0.8
Results for Huxley '57 model
.
X

< 0 X

= -h/2
X

= h/2
(a)
(c)
(b)
(a)
(b)
(c)
As velocity increases (V>0), probability of attachment of the A site
to the myosin can be above zero for X<0 because XBs may attach
between X=0 and X=h and be dragged to negative distortions.
n(h/2) ~ 0.4 n(-h/2) ~ 0
Results for Huxley '57 model
.
X

< 0 X

= -h/2
X

= h/2
(a)
(c)
(b)
(a)
(b)
(c)
As velocity increases (V>0), the average distortion of the
attached XBs decreases (less positive or more negative). At
V
max
the "pullers" (X>0, i.e. (a)) and "dragger" (X<0, i.e. (b))
cancel so that net tension T = 0. Detached XBs don't contribute.
n(-h/2) ~ 0.1
n(h/2) ~ 0.15
Now we want to generate a Force-Velocity relation.
Velocity is an input parameter, and force is computed.
Must define force per single XB as
Where x is the distortion (= distance from A site to
equilibrium position of attached crossbridge)
Now we want to compute total tension as a the sum of the
the contributions of all the XBs. To do this, we need to
compute an expected value that is analogous to
average value. First define an expected value as:
expected value of u
value of u
probability density
function of finding u
kx force
XB
=
}
>= < du u u u ) pdf(
In our case, we want expected value of tension for all A
sites, both attached and detached. We can write
expected value as:
Force of attached A site
Attached A sites
True p.d.f. of all A site being at distance = x
| | dx x n x h x n kx T
XB
}


)
`

- + >= < ) (

) (

0 ) (

Detached A sites
| | dx x n x h x n
}


)
`

+ = ) (

) (

) (

1
Force of detached A site
) (

) ( ) (

x h x n x n - =
A p.d.f. describing likelihood
of A sites being distance x
from the nearest equilibrium
XB position
Model assumes is constant over all possible x
values between -l/2 and l/2 as shown below:
l/2
-l/2
1/l
x
h

A condition probability of an A
site having an attached XB given
its distance is x from the nearest
equilibrium XB position
h

Recall these features of the model:


otherwise
l x l l x n
x n
2 / 2 /
;
;
0
/ ) (
) (

< <

=
Multiplying the terms produces:
dx x n kx T
XB
}


>= < ) (

dx x n
l
kx
l
l
}

=
2 /
2 /
) (
Substitute for n(x) and integrate to get:

(
(

|
|
.
|

\
|
+
+
+
>= <

| |
|
V
g
g f
e
V
l
kh
g f
f
T
V
XB
2
2
1 1
2
1 1
1
2
1
1 ) 1 ( 1
2
Then substituting into expected value of force:

(
(

|
|
.
|

\
|
+
+ =
> <
> <
=

| |
|
V
g
g f
e
V
T
T
T T
V
XB
XB
2
2
1 1
max
max
2
1
1 ) 1 ( 1 /
For isometric force, set v=0 to get:
l
kh
g f
f
T
XB
2
2
1 1
1
max
+
>= <
Now normalize force by isometric force to get:
) (
1 1
g f
S
h
+ = |
16
3
1 1
1
=
+ g f
g
919 . 3
1 1
2
=
+ g f
g
These parameter give best fit to
experimental data at right
"All models are wrong, but some are useful."
-George Box
Successes of model -
- Good basic framework for cycling XB distribution
- Reproduces Force Velocity relationship
- Reproduces energy use vs. tension relationship
- Superb first attempt given the knowledge of the
system at the time
Problems -
- XB cycle is simplistic
- Restrictive set of conditions
- isotonic, constant velocity
- full activation
- Cycling rate increases with lengthening causing increased
ATP usage in disagreement with experimental results