Computer modelling of an artificial cell undergoing osmotic shock

Researchers from the University of Groningen, headed by Dr. Martti
Louhivuori and Prof. Siewert-Jan Marrink, have simulated the effect of an
osmotic shock on a proto-type cell containing a nano-valve in the form of
a mechanosensitive protein channel. The simulations show the
spontaneous gating of the protein channel and subsequent release of
internal content, opening the way toward in-silico design of biomimetic
nano-containers as drug delivery vehicles. The research has been published
in Proc. Nat. Acad. Sci. USA.

‘It is quite remarkable that a single channel is capable of relaxing an osmotically
stressed liposome in less than a millisecond’, says researcher Martti Louhivuori.
‘This study demonstrates that the simulation of a bio-mimetic nano-container is
feasible and provides a computational tool for the rational design of programmable
drug delivery vehicles.’

Mechanosensitive channels as nano-valves

Mechano-sensitive channels are membrane-embedded proteins that react to a
sudden increase in membrane tension by forming trans-membrane pores. In
bacteria they act as safety valves preventing the membrane to rupture upon an
osmotic shock. However, these channels can also be reconstituted into small
artificial cells, liposomes, in which they can act as nano-valves releasing the
internal content upon their gating. Here we model the gating of a particular
mechanosensitive channel, MscL, embedded in an osmotically stressed liposome
using molecular dynamics simulations. For the first time we are able to capture
the tension induced gating process of a mechanosensitive channel at near-atomic
resolution.

MscL activates at the limit of membrane elasticity

It is insightful to compare what happens to the liposome with or without the MscL
channel being present (see figure). Without the channel, the liposome grows until
a threshold is reached and then it simply bursts, venting excess solvent out. In the
presence of MscL, however, the uncontrolled rupture of the liposome is prevented.
Just before the liposome would burst, the channel opens, and dissipation of the
internal pressure occurs by the release of excess solvent through the activated
membrane channel.

Liposomal stress is relaxed on a sub-millisecond time-scale

After channel opening the simulation has been extended over a period of 40
microseconds to monitor the further release of the internal content. During this
period the osmotic pressure in the liposome gradually decreases. Based on the
observed flux through the channel we estimate that it would take 0.1 milliseconds
for the liposome to be fully relaxed. Playing with lipid composition and engineered
channel mutants, the gating properties of the channel can in principle be varied.
Our study opens the way to design, in-silico, a bio-inspired system with optimal
conditions for controlled drug release.

Note for the press

More information:
- Prof. Siewert-Jan Marrink, tel. 050-363 4457, e-mail s.j.marrink rug.nl
- Dr. Martti Louhivuori, tel. 050-363 4339, e-mail m.j.louhivuori rug.nl

Publication: Release of content through mechano-sensitive
gates in pressurised liposomes, Martti Louhivuori, H. Jelger Risselada, Erik van
der Giessen, Siewert J. Marrink.

http://www.pnas.org/content/early/2010/10/25/1001316107.abstract