Computer Simulations of Mechano-Chemical Networks Choreographing Actin Dynamics in Cell Motility - Computational Modeling of Biological Systems - page 243

fluctuations are important. Capping process is then a discrete (either capped or
uncapped) random noise. It is also slow, due to low capping protein concentration.
The discreteness and slowness make capping process act as a random switch
between two fast processes of growth and retraction. The filopodium thus acts as
an amplifier of capping protein binding noise, making it visible on macroscopic
temporal ( 1m) scales. This high susceptibility to tiny

fluctuations may be profitably exploited for the sensorial role of filopodia [ 34 ].
It should be noted that in order to describe such effects, the model has to be
stochastic and microscopic and include molecular details, because it is molecular
noise of chemical binding that translates into macroscopic mechanical observables
through mechano-chemical amplification.

100 s) and spatial (

3.4 Transport

Modeling the interconversion of actin fluxes in a filopodium suggests that the
diffusional flux can not sustain the growth above several microns (at biological actin
concentrations and retrograde flow speed values), even if the number of polymer-
izing filaments is decreased by capping proteins [ 19 , 20 , 34 ]. In some experiments
filopodia can grow over 80 microns, so there have to be other mechanisms altering
actin fluxes to make such growth possible [ 50 ]. Also, diffusional flux is not enough
to account for the experimentally observed growth speeds of about 10 m/min [ 50 ].
Modeling various mechanisms of flux regulation (even such that are not at present
proven to exist from experiments) allows to consider the potential effectiveness
and likelihood of various possible scenarios and then help to focus experimental
research on the most plausible mechanisms. Since modeling requires less resources
than experiments, this is a great way to move forward our understanding of the
regulatory processes in filopodia.
Downregulating polymerization flux or retrograde flow will slow down growth
and/or retraction speeds. Therefore, to provide enough actin for long, fast growing
and retracting filopodia, additional flux of G-actin to the filopodial tip is needed
besides diffusion. A “standard” biological solution for underperformance in diffu-
sional transport is the use of molecular motors. Some molecular motors can walk
on actin filaments in a directed fashion, that is, the shift in their spatial position is
proportional to time, not square root of time, as in diffusion. They can bind cargo,
and drag it along while walking, thus realizing active transport of the cargo [ 53 , 54 ].
In fact, Myosin X molecular motors, which can walk along actin filaments, have
been observed inside filopodia and shown to influence filopodial formation [ 55 ].
Their exact role is not known, and they have not been observed to carry G-actin
experimentally. This is where the modeling can help: it is straightforward to
introduce into simulations myosins with ability to walk, diffuse, and bind G-actin,
and see if it will considerably increase the filopodial lengths or growth speeds.
The picture of active transport suggested by cartoons in biology textbooks shows
cargo loaded onto motors which walk forward and unload cargo at the destination,