Researchers from the University of Groningen, headed by Dr. MarttiLouhivuori and Prof. Siewert-Jan Marrink, have simulated the effect of anosmotic shock on a proto-type cell containing a nano-valve in the form ofa mechanosensitive protein channel. The simulations show thespontaneous gating of the protein channel and subsequent release ofinternal content, opening the way toward in-silico design of biomimeticnano-containers as drug delivery vehicles. The research has been publishedin Proc. Nat. Acad. Sci. USA.
‘It is quite remarkable that a single channel is capable of relaxing an osmoticallystressed liposome in less than a millisecond’, says researcher Martti Louhivuori.‘This study demonstrates that the simulation of a bio-mimetic nano-container isfeasible and provides a computational tool for the rational design of programmabledrug delivery vehicles.’
Mechano-sensitive channels are membrane-embedded proteins that react to asudden increase in membrane tension by forming trans-membrane pores. Inbacteria they act as safety valves preventing the membrane to rupture upon anosmotic shock. However, these channels can also be reconstituted into smallartificial cells, liposomes, in which they can act as nano-valves releasing theinternal content upon their gating. Here we model the gating of a particularmechanosensitive channel, MscL, embedded in an osmotically stressed liposomeusing molecular dynamics simulations. For the first time we are able to capturethe tension induced gating process of a mechanosensitive channel at near-atomicresolution.
It is insightful to compare what happens to the liposome with or without the MscLchannel being present (see figure). Without the channel, the liposome grows untila threshold is reached and then it simply bursts, venting excess solvent out. In thepresence of MscL, however, the uncontrolled rupture of the liposome is prevented.Just before the liposome would burst, the channel opens, and dissipation of theinternal pressure occurs by the release of excess solvent through the activatedmembrane channel.
After channel opening the simulation has been extended over a period of 40microseconds to monitor the further release of the internal content. During thisperiod the osmotic pressure in the liposome gradually decreases. Based on theobserved flux through the channel we estimate that it would take 0.1 millisecondsfor the liposome to be fully relaxed. Playing with lipid composition and engineeredchannel 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 optimalconditions for controlled drug release.
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-sensitivegates in pressurised liposomes, Martti Louhivuori, H. Jelger Risselada, Erik vander Giessen, Siewert J. Marrink.
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