Загальна теорія іонних каналів з багатократною заселеністю

У статті представлений загальний теоретичний підхід, що дозволяє описати провідність іонних каналів з множинною заселеністю. Він базується на реальній структурі калієвого каналу KcsA, але не обмежується даним каналом. Показано, що рух іонів у селективному фільтрі каналу є істотно колективним і може бути редукованим до руху єдиної квазічастинки - квазііону. Концепція квазііонів дозволяє пояснити явище безбар'єрної виштовхувальної провідності в селективному фільтрі та уникнути повного опису руху індивідуальних іонів у багатоіонному каналі, що значно спрощує задачу. Показано, що квазііони є фактичними переносниками заряду в каналі.We present a general theoretical approach, which explains the conductance in the ion channel with multiple occupancy. The model is based on the design of KcsA K* channel, but not limited to it. We show that the motion of the ions in the selective filter is concerted and can be reduced to the motion of a single quasiparticle called quasi-ion. The concept of quasi-ions provides an elegant explanation of barrier-less "knock-on" conduction in the selectivity filter and allows us to avoid explicit description of the motion of individual ions in the multi-ion channel. The quasi-ions perform actual charge transfer in the channel

The fate of therapeutic nanoparticles in a model biological medium: interactions with serum albumin

International audienceIn the field of nanomedicine, nanostructured nanoparticles (NPs) made of self-assembling prodrugs emerged in the recent years. In particular, the squalenoylation concept has been applied to several therapeutic agents with promising results. These nanoparticles allow a high encapsulation rate of the active principle, the protection from quick degradation, and a good control of the targeting and release. Beyond the high potential of these Nps, there is still a need for a better understanding of their evolution in biological media. The colloidal stability of the NPs, their interaction with proteins and how the internal NPs nanostructure influences their efficacy are essential questions to go towards a better understanding of the mechanism of their fate in the organism (nanoparticle disassembly, targeting etc ...). We choose to investigate these questions on the particular case of Squalene-Adenosine (SqAd) nanoparticles, whose neuroprotective effect has already been demonstrated in murine models and model biological media . From the combination of multiple techniques (neutron and x-ray scattering, cryogenic transmission electron microscopy, circular dichroism, fluorescence spectroscopy, isothermal titration calorimetry and OFT calculations) we investigate the interactions between the SqAd Nps and the serum albumin, one of the main proteic components of blood plasma. We show that albumin affects the colloidal stability of the nanoparticles but also partially disassembles the nanoparticles by forming SqAd-albumin complexes. Albumin should thus playa crucial role in the transport of the prodrug, while the nanoparticles would act as a circulating reservoir in the blood stream

Comparative analysis of essential collective dynamics and NMR-derived flexibility profiles in evolutionarily diverse prion proteins

Collective motions on ns-µs time scales are known to have a major impact on protein folding, stability, binding and enzymatic efficiency. It is also believed that these motions may have an important role in the early stages of prion protein misfolding and prion disease. In an effort to accurately characterize these motions and their potential influence on the misfolding and prion disease transmissibility we have conducted a combined analysis of molecular dynamic simulations and NMR-derived flexibility measurements over a diverse range of prion proteins. Using a recently developed numerical formalism, we have analyzed the essential collective dynamics (ECD) for prion proteins from eight different species including human, cow, elk, cat, hamster, chicken, turtle and frog. We also compared the numerical results with flexibility profiles generated by the random coil index (RCI) from NMR chemical shifts. Prion protein backbone flexibility derived from experimental NMR data and from theoretical computations show strong agreement with each other, demonstrating that it is possible to predict the observed RCI profiles employing the numerical ECD formalism. Interestingly, flexibility differences in the loop between second b strand (S2) and the second a helix (HB) appear to distinguish prion proteins from species that are susceptible to prion disease and those that are resistant. Our results show that the different levels of flexibility in the S2-HB loop in various species are predictable via the ECD method, indicating that ECD may be used to identify disease resistant variants of prion proteins, as well as the influence of prion proteins mutations on disease susceptibility or misfolding propensity