Phospholamban inhibits the cardiac calcium pump by interrupting an allosteric activation pathway.

Phospholamban (PLB) is a transmembrane micropeptide that regulates the sarcoplasmic reticulum Ca2+-ATPase (SERCA) in cardiac muscle, but the physical mechanism of this regulation remains poorly understood. PLB reduces the Ca2+ sensitivity of active SERCA, increasing the Ca2+ concentration required for pump cycling. However, PLB does not decrease Ca2+ binding to SERCA when ATP is absent, suggesting PLB does not inhibit SERCA Ca2+ affinity. The prevailing explanation for these seemingly conflicting results is that PLB slows transitions in the SERCA enzymatic cycle associated with Ca2+ binding, altering transport Ca2+ dependence without actually affecting the equilibrium binding affinity of the Ca2+-coordinating sites. Here, we consider another hypothesis, that measurements of Ca2+ binding in the absence of ATP overlook important allosteric effects of nucleotide binding that increase SERCA Ca2+ binding affinity. We speculated that PLB inhibits SERCA by reversing this allostery. To test this, we used a fluorescent SERCA biosensor to quantify the Ca2+ affinity of non-cycling SERCA in the presence and absence of a non-hydrolyzable ATP-analog, AMPPCP. Nucleotide activation increased SERCA Ca2+ affinity, and this effect was reversed by co-expression of PLB. Interestingly, PLB had no effect on Ca2+ affinity in the absence of nucleotide. These results reconcile the previous conflicting observations from ATPase assays versus Ca2+ binding assays. Moreover, structural analysis of SERCA revealed a novel allosteric pathway connecting the ATP- and Ca2+-binding sites. We propose this pathway is disrupted by PLB binding. Thus, PLB reduces the equilibrium Ca2+ affinity of SERCA by interrupting allosteric activation of the pump by ATP.

Sensing membrane voltage by reorientation of dipolar transmembrane peptides.

Membrane voltage plays a vital role in the behavior and functions of the lipid bilayer membrane. For instance, it regulates the exchange of molecules across the membrane through transmembrane proteins such as ion channels. In this paper, we study the membrane voltage-sensing mechanism, which entails the reorientation of α-helices with a change in the membrane voltage. We consider a helix having a large electrical macrodipole embedded in a lipid bilayer as a model system. We performed extensive molecular dynamics simulations to study the effect of variation of membrane voltage on the tilt angle of peptides and ascertain the optimal parameters for designing such a voltage-sensing peptide. A theoretical model for the system is also developed to investigate the interplay of competing effects of hydrophobic mismatch and dipole-electric field coupling on the tilt of the peptide and further explore the parameter space. This work opens the possibility for the design and fabrication of artificial dipolar membrane voltage-sensing elements for biomedical applications.

Rectification of twitching bacteria through narrow channels: A numerical simulations study.

Bacteria living on surfaces use different types of motility mechanisms to move on the surface in search of food or to form microcolonies. Twitching is one such form of motility employed by bacteria such as Neisseria gonorrhoeae, in which the polymeric extensions known as type IV pili mediate its movement. Pili extending from the cell body adhere to the surface and pull the bacteria by retraction. The bacterial movement is decided by the two-dimensional tug-of-war among the pili attached to the surface. Natural surfaces on which these microcrawlers dwell are generally spatially inhomogeneous and have varying surface properties. Their motility is known to be affected by the topography of the surfaces. Therefore, it is possible to control bacterial movement by designing structured surfaces which can be potentially utilized for controlling biofilm architecture. In this paper, we numerically investigate the twitching motility in a two-dimensional corrugated channel. The bacterial movement is simulated by two different models: (a) a detailed tug-of-war model which extensively describe the twitching motility of bacteria assisted by pili and (b) a coarse-grained run-and-tumble model which depicts the motion of wide-ranging self-propelled particles. The simulation of bacterial motion through asymmetric corrugated channels using the above models show rectification. The bacterial transport depends on the geometric parameters of the channel and inherent system parameters such as persistence length and self-propelled velocity. In particular, the variation of the particle current with the geometric parameters of the microchannels shows that one can optimize the particle current for specific values of these parameters.

Tailored morphologies in two-dimensional ferronematic wells.

We focus on a dilute uniform suspension of magnetic nanoparticles in a nematic-filled micron-sized shallow well with tangent boundary conditions as a paradigm system with two coupled order parameters. This system exhibits spontaneous magnetization without magnetic fields. We numerically obtain the stable nematic and associated magnetization morphologies, induced purely by the geometry, the boundary conditions, and the coupling between the magnetic nanoparticles and the host nematic medium. Our most striking observations pertain to domain walls in the magnetization profile, whose location can be manipulated by the coupling and material properties, and stable interior and boundary nematic defects, whose location and multiplicity can be tailored by the coupling too. These tailored morphologies are not accessible in uncoupled systems and can be used for multistable systems with singularities and stable interfaces.

Magnetic nanoparticles in a nematic channel: A one-dimensional study.

We study a dilute suspension of magnetic nanoparticles in a nematic-filled channel and how the spatial magnetization M can be tailored by the nematic anisotropy. We study the spatial configurations as stable critical points of a generalized phenomenological energy for a dilute ferronematic in the absence of external magnetic fields. We show how spatial inhomogeneities in the equilibrium nematic profile, induced by confinement and boundary effects, generate nonzero spatially inhomogeneous magnetization profiles in the system. Depending on the magnetonematic coupling energy, M can either follow the nematic profile for large coupling or exhibit distinct polydomain structures separated by defect lines for weak coupling and low temperatures. Some exact solutions for prototypical situations are also obtained.

Twitching motility of bacteria with type-IV pili: Fractal walks, first passage time, and their consequences on microcolonies.

A human pathogen, Neisseria gonorrhoeae (NG), moves on surfaces by attaching and retracting polymeric structures called Type IV pili. The tug-of-war between the pili results in a two-dimensional stochastic motion called twitching motility. In this paper, with the help of real-time NG trajectories, we develop coarse-grained models for their description. The fractal properties of these trajectories are determined and their influence on first passage time and formation of bacterial microcolonies is studied. Our main observations are as follows: (i) NG performs a fast ballistic walk on small time scales and a slow diffusive walk over long time scales with a long crossover region; (ii) there exists a characteristic persistent length l_{p}^{*}, which yields the fastest growth of bacterial aggregates or biofilms. Our simulations reveal that l_{p}^{*}∼L^{0.6}, where L×L is the surface on which the bacteria move; (iii) the morphologies have distinct fractal characteristics as a consequence of the ballistic and diffusive motion of the constituting bacteria.