Phase offset between arterial pulsations and subarachnoid space pressure fluctuations are unlikely to drive periarterial cerebrospinal fluid flow.

Circulation of fluid through the central nervous system maintains fluid homeostasis and is involved in solute clearance. The glymphatic system is hypothesised to facilitate waste clearance in the brain, with inflow via periarterial spaces, bulk flow through the parenchyma, and outflow via perivenous spaces. The driving force for this mechanism is unknown. Previous modelling in the spinal cord suggests that timing offsets between arterial and subarachnoid space pressure pulses can enable net inflow in perivascular spaces (PVS). This study adapted the spinal pulse offset mechanism to the brain and simulated movement of tracer particles used in experiments. Both bulk flow and diffusive movement of tracer were simulated. Intracranial pressure pulses were applied to one end of a 300-µm-long perivascular space combined with a moving arterial wall simulating arterial pulsations. The simulations indicate the pulse offset mechanism can enable net inflow via PVS; however, it is unknown whether the temporal offset required is physiologically realistic. Increasing the positive component of the ICP (intracranial pressure) pulse increased net flow. Tracer particles driven by bulk flow reached the outlet of the PVS with a net speed of ~ 16 µm/s when the permeability was two orders of magnitude higher than values in the literature. These particles were unable to penetrate into the parenchyma in the absence of diffusion. Dispersion dominated tracer movement in the parenchyma. Further research is required to reconcile discrepancies between these results, and both experimental and computational studies.

Cell membrane mechanics and mechanosensory transduction.

The rapid progress in mechanobiology has brought together many scientific and engineering disciplines to work hand in hand toward better understanding of the role that mechanical force plays in functioning and evolution of different forms of life. New tools designed by engineers helped to develop new methods and techniques for investigation of mechanical properties of biological cells and tissues. This multidisciplinary approach made it clear that cell mechanics is tightly linked to intracellular signaling pathways, which directly regulate gene expression in response to mechanical stimuli originating outside or inside the cells. Mechanical stimuli act on mechanoreceptors which convert these stimuli into intracellular signals. In this chapter, we review the current knowledge about cell mechanics and the role cell mechanics plays for the function of mechanosensitive ion channels as a special class of mechanoreceptors functioning as molecular transducers of mechanical stimuli on a millisecond timescale.

Computational modelling of fluid and solute transport in the brain.

The glymphatic system is proposed to be a unidirectional fluid and solute circulation pathway in the brain involving transport through perivascular spaces, brain interstitium and glial cells. Some aspects of the glymphatic hypothesis are controversial, particularly the outflow pathway, and little is known about the forces that govern such fluid transport at each stage. Computational and mathematical modelling approaches can be valuable for testing hypotheses and are a useful adjunct to experimental research in this field. This article presents an overview of computational modelling studies associated with glymphatic fluid transport in the brain, from fluid inflow, transparenchymal transport and outflow. A broad range of modelling approaches have been used to investigate fluid and solute transport from purely analytical models to hydraulic resistance networks and computational fluid dynamics models. Most of the modelling attention has focused on periarterial inflow and transport through the parenchyma. Collectively these studies suggest that arterial pulsation is unlikely to be the sole inflow driving force, and diffusion is most likely the dominant mode of transport in the parenchymal extracellular spaces. Models of efflux are limited and have not been able to shed light on the driving forces for fluid outflow from the central nervous system.

Tuning ion channel mechanosensitivity by asymmetry of the transbilayer pressure profile.

Mechanical stimuli acting on the cellular membrane are linked to intracellular signaling events and downstream effectors via different mechanoreceptors. Mechanosensitive (MS) ion channels are the fastest known primary mechano-electrical transducers, which convert mechanical stimuli into meaningful intracellular signals on a submillisecond time scale. Much of our understanding of the biophysical principles that underlie and regulate conversion of mechanical force into conformational changes in MS channels comes from studies based on MS channel reconstitution into lipid bilayers. The bilayer reconstitution methods have enabled researchers to investigate the structure-function relationship in MS channels and probe their specific interactions with their membrane lipid environment. This brief review focuses on close interactions between MS channels and the lipid bilayer and emphasizes the central role that the transbilayer pressure profile plays in mechanosensitivity and gating of these fascinating membrane proteins.

Structural Dynamics of the MscL C-terminal Domain.

The large conductance mechanosensitive channel (MscL), acts as an osmoprotective emergency valve in bacteria by opening a large, water-filled pore in response to changes in membrane tension. In its closed configuration, the last 36 residues at the C-terminus form a bundle of five α-helices co-linear with the five-fold axis of symmetry. Here, we examined the structural dynamics of the C-terminus of EcMscL using site-directed spin labelling electron paramagnetic resonance (SDSL EPR) spectroscopy. These experiments were complemented with computational modelling including molecular dynamics (MD) simulations and finite element (FE) modelling. Our results show that under physiological conditions, the C-terminus is indeed an α-helical bundle, located near the five-fold symmetry axis of the molecule. Both experiments and computational modelling demonstrate that only the top part of the C-terminal domain (from the residue A110 to E118) dissociates during the channel gating, while the rest of the C-terminus stays assembled. This result is consistent with the view that the C-terminus functions as a molecular sieve and stabilizer of the oligomeric MscL structure as previously suggested.

Pulling MscL open via N-terminal and TM1 helices: A computational study towards engineering an MscL nanovalve.

There are great opportunities in the manipulation of bacterial mechanosensitive (MS) ion channels for specific and targeted drug delivery purposes. Recent research has shown that these ion channels have the potential to be converted into nanovalves through clever use of magnetic nanoparticles and magnetic fields. Using a combination of molecular dynamics (MD) simulations and the finite element (FE) modelling, this study investigates the theoretical feasibility of opening the MscL channel (MS channel of large conductance of E. coli) by applying mechanical force directly to its N-terminus. This region has already been reported to function as a major mechanosensor in this channel. The stress-strain behaviour of each MscL helix was obtained using all atom MD simulations. Using the same method, we simulated two models, the wild-type (WT) MscL and the G22N mutant MscL, both embedded in a POPE lipid bilayer. In addition to indicating the main interacting residues at the hydrophobic pore, their pairwise interaction energies were monitored during the channel gating. We implemented these inputs into our FE model of MscL using curve-fitting codes and continuum mechanics equations. In the FE model, the channel could be fully opened via pulling directly on the N-terminus and bottom of TM1 by mutating dominant van der Waals interactions in the channel pore; otherwise the stress generated on the channel protein can irreversibly unravel the N-secondary structure. This is a significant finding suggesting that applying force in this manner is sufficient to open an MscL nanovalve delivering various drugs used, for example, in cancer chemotherapy. More importantly, the FE model indicates that to fully operate an MscL nanovalve by pulling directly on the N-terminus and bottom of TM1, gain-of-function (GOF) mutants (e.g., G22N MscL) would have to be employed rather than the WT MscL channel.