Biomedical Engineering Reference
In-Depth Information
motor complex [
79
] and reduced speed for a complex of two myosin V motors [
66
].
Reduced velocity has also been observed in microtubule gliding assays at high motor
density with certain kinesin constructs with reduced flexibility [
11
,
24
].
Our recent analysis of such interference effects has indicated the importance of
the dynamic nature of these forces [
7
,
8
]: Typically a motor will bind to the filament
in a force-free fashion. The force between the motors is then built up by the stochastic
stepping. The generation of forces of the order of the stall force (where a motor stops
to step) or of the detachment force (the characteristic force scale for the unbinding
rate) thus occurs over some characteristic timescales. These timescales have to be
compared to the timescale for spontaneous unbinding, which provides a measure for
the time the motors have to build up strain. If the time for spontaneous unbinding is
very small, typically motors unbind before substantial strain is generated and thus
interference effects are rather weak. A related issue arises when an external force is
applied to a multi-motor complex: Only motors bound to the filament experience the
load. When an additional motor binds to the filament, it will initially not experience
any force and thus it will take some time until the force is actually shared equally
among the bound motors. Equal force sharing is only reached if unbinding of motors
is slower than the characteristic timescale for the equilibration of force sharing.
Another question related to the stochastic stepping of the motors concerns the size
of the observed steps. If the motors do not move in a synchronised fashion, steps that
correspond to fractions of the single-motor step can be expected. This has indeed
been observed in gliding assays for two motors, but not for three motors [
58
]. This
observation has been attributed to nonequal force sharing between three motors [
58
]
and to nonlinear elastic coupling between the motors [
60
].
Yet another longstanding challenge is the question how force is actually exerted on
the molecules. This question is directly related to the spatial structure of the molecule.
Force is typically exerted via the tail domain of the motor and somehow transmitted
to the nucleotide binding pocket and to the microtubule binding site. How this force
transmission occurs is not very clear. Important questions in this context are: Does
the force experienced by the nucleotide binding pocket depend on the direction of
the force in three dimensions? Is the commonly used one-dimensional description
by a force along the direction of motion reasonably accurate? If not, which direction
of force is characteristic in multi-motor complexes?
We conclude this section on the challenges to modeling and computation by a few
general remarks. One rationale for using a palette of models at different scales, each
appropriate for certain research questions, rather than a single model that describes
everything, is the maxim attributed to Einstein to make things as simple as possible,
but not simpler.
1
Doing so allows one to identify the key ingredients for certain
phenomena to arise, while still being able to make quantitative predictions. This does
not mean that further simplifications are useless. Further simplification may still be
of use to provide a theoretical perspective on the core mechanisms. Nevertheless,
one needs to keep in mind that every theoretical description is based on certain
1
A discussion of the origin of the quote can be found at
http://quoteinvestigator.com/2011/05/13/
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