[Murg] [>Htech] physorg: largish membrane fusion simulations (fwd from alito@organicrobot.com)

[Eugen Leitl]

----- Forwarded message from Alejandro Dubrovsky <alito at organicrobot.com> -----

From: Alejandro Dubrovsky <alito at organicrobot.com>
Date: Tue, 08 Mar 2005 03:27:07 +1000
To: transhumantech <transhumantech at yahoogroups.com>
Subject: [>Htech] physorg: largish membrane fusion simulations
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(
http://www.physorg.com/news3275.html
)

Scientists use new simulation methods to observe single events of
membrane fusion with molecular resolution

March 07, 2005

The fusion of membranes is essential for many processes in the human
body, for instance, in the communication between nerve cells. A single
fusion event occurs on the nanometer scale and takes less than a
millisecond. Using computer simulations, scientists at the Max Planck
Institute of Colloids and Interfaces have now been able to observe
single fusion events with molecular resolution. The simulations are
based on new computer algorithms by which one can investigate two large
membranes which contain more that ten thousand lipid molecules
surrounded by about three million water molecules. These simulations
reveal that the fusion process can be controlled by the initial tensions
within the membranes. Fusion occurs only at intermediate tensions but,
when it occurs, it happens extremely quickly and is completed within 200
nanoseconds.

Membrane fusion is a ubiquitous process of life. A prominent example is
provided by the fusion of synaptic vesicles to the outer membranes of
nerve cells. This fusion process is responsible for the release of
neurotransmitters into the synaptic cleft and, thus, for the
communication between these cells. In this way, membrane fusion provides
the molecular basis for all our thoughts. Another example is viral
infection. Many viruses, such as the influenza or the HIV virus, hide
behind a membrane that they have "stolen" from an infected cell. Using
this membrane, the viruses can fuse with new cells which become infected
as well.

Other examples for membrane fusion include: the fusion of egg and sperm
cell during sexual reproduction; the growth of skeletal muscle cells via
the fusion of smaller precursor cells (myoblasts); secretion processes
such as the release of histamine from mast cells which represents the
molecular event underlying many allergic reactions. In addition, we find
many more fusion processes when we look at the heavy membrane traffic
that is present in all human cells. Indeed, each of these cells contains
a huge number of vesicles and other compartments (organelles) that are
enclosed in membranes. Many of these vesicles act as transport vehicles
that shuttle between the different compartments and deliver their cargo
via membrane fusion.

In spite of its ubiquity, the molecular mechanisms underlying the
process of membrane fusion are still rather mysterious. There are
several reasons for this. First, membrane fusion occurs in the
nanoregime and is characterized by length scales between 2 and 20
nanometers. Some experimental tools such as electron microscopy or
scanning force microscopy are able to resolve these length scales but
only if the membranes are frozen or immobilized and, thus, are no longer
able to fuse. Second, a single fusion event represents a relatively fast
process. In fact, fusion is so fast that it has so far not been possible
to experimentally measure the corresponding fusion time. Third, the
fusion of biomembranes involves many different types of molecules,
lipids and proteins, which has led to a long and ongoing controversy
about the relative importance of these different molecular species for
the fusion process.

Using computer simulations, scientists at the Max Planck Institute of
Colloids and Interfaces have recently been able to directly observe
single fusion events with molecular resolution and to measure the
corresponding fusion times. These simulations are based on new
algorithms (Dissipative Particle Dynamics - a particle model which
allows the simulation of complex fluids at mesoscopic scales) by which
one can include a huge number of molecules - in the present case, about
ten thousand lipid molecules and about three million water molecules.
This makes it possible to study the interaction of a lipid vesicle,
which has a diameter of 28 nanometer, with a planar lipid membrane with
an area of 50 x 50 square nanometers and a water volume of 50 x 50 x 50
cubic nanometers (see Figure).

When the simulation starts, the vesicle and planar membrane are
separated by a thin water layer of 1.5 nanometers. Each membrane
consists of a molecular bilayer, i.e., two layers of lipid molecules
that are arranged in such a way that the hydrophilic head groups shield
the hydrophobic lipid tails from the water. After about 80 nanoseconds
(first snapshot in Figure), the membranes have moved into contact by
Brownian motion. During the next 60 nanoseconds, the lipid molecules
within the contact zone rearrange themselves in such a way that the two
membranes undergo hemifusion, i.e., the two bilayers have merged into a
single one. This molecular intermingling process seems to represent a
new fusion step which has not been reported previously. The resulting
hemifused state is rather short-lived since it ruptures relatively fast.
This latter step leads to a complete fusion pore that connects the two
membranes in a smooth neck--like fashion. The water within the vesicle
can then flow through the fusion pore and, in this way, is released from
the vesicle compartment.

One important insight provided by these simulations is that the fusion
process can be controlled by the initial tensions within the two
membranes. For a given membrane, this tension depends on the ratio of
the membrane area and the number of assembled lipid molecules. No fusion
is observed, within a couple of microseconds, when vesicle and planar
membrane are initially relaxed. Instead, the vesicle adheres to and
spreads onto the planar membrane. If the vesicle membrane is initially
too tense, it ruptures before fusion with the second membrane can occur.
Likewise, a large initial tension within the planar membrane leads to
premature rupture of this latter membrane. As a consequence, fusion can
only occur at intermediate values of the membrane tensions. However,
even at those intermediate tensions, only about 55 percent of all fusion
attempts lead to successful fusion events. The remaining unsuccessful
attempts lead once again to membrane rupture or to stable hemifused
states.

Each successful fusion event can be characterized by its fusion time,
i.e., by the time from first membrane contact to the appearance of a
complete fusion pore. This time represents a random variable since it
differs from fusion event to fusion event even if the initial membrane
tensions are the same. The statistical distribution of resulting fusion
times shows two remarkable features. First, the fusion time
distributions for different tensions have significant overlap and are
all centered around an average fusion time between 200 and 300
nanoseconds. Second, no fusion event has been observed with a fusion
time between 350 nanoseconds and 2 microseconds. This cut-off in the
fusion time distribution is related to the stabilization of hemifused
membranes at lower tension values.

The fusion of biological membranes is regulated by fusion proteins which
are anchored in these membranes. It is generally believed that this
regulation is based on conformational changes of these proteins which
exert localized tensions and bending moments onto the membranes. In
general, different fusion proteins should lead to different force
patterns acting on the membranes. Such localized force patterns can be
included in the computer models and have been found to induce membrane
fusion as well. In fact, using localized force patterns, the fusion
process is still characterized by a fusion time in the order of 200
nanoseconds but this process is now more reliable and less random, an
obvious advantage for biological fusion processes.

The extension of these simulation studies to multi-component membranes
should lead to a deeper understanding of membrane fusion in vivo. It
will then be possible to construct biomimetic model systems that are
based on the same molecular mechanisms. It seems rather attractive, for
example, to use such systems for smart drug delivery. The vision is to
enclose the drugs in vesicles that adhere to the unhealthy cells, fuse
with these cells, and deliver their cargo only to those cells in a
controlled manner.

Original work:

Julian Shillcock and Reinhard Lipowsky
Tension-induced fusion of bilayer membranes and vesicles
Nature Materials (Advanced Online Publication, February 13, 2005)

Reinhard Lipowsky
Biomimetic membrane modelling - Pictures from the twilight zone
Nature Materials 3, 589 - 591 (2004)

Source: Max Planck Institute 



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