The Role of the Dielectric Barrier in Narrow Biological Channels: a Novel Composite Approach to Modeling Single-channel Currents

A composite continuum theory for calculating ion current through a protein channel of known structure is proposed, which incorporates information about the channel dynamics. The approach is utilized to predict current through the Gramicidin A ion channel, a narrow pore in which the applicability of conventional continuum theories is questionable. The proposed approach utilizes a modified version of Poisson-Nernst-Planck (PNP) theory, termed Potential-of-Mean-Force-Poisson-Nernst-Planck theory (PMFPNP), to compute ion currents. As in standard PNP, ion permeation is modeled as a continuum drift-diffusion process in a self-consistent electrostatic potential. In PMFPNP, however, information about the dynamic relaxation of the protein and the surrounding medium is incorporated into the model of ion permeation by including the free energy of inserting a single ion into the channel, i.e., the potential of mean force along the permeation pathway. In this way the dynamic flexibility of the channel environment is approximately accounted for. The PMF profile of the ion along the Gramicidin A channel is obtained by combining an equilibrium molecular dynamics (MD) simulation that samples dynamic protein configurations when an ion resides at a particular location in the channel with a continuum electrostatics calculation of the free energy. The diffusion coefficient of a potassium ion within the channel is also calculated using the MD trajectory. Therefore, except for a reasonable choice of dielectric constants, no direct fitting parameters enter into this model. The results of our study reveal that the channel response to the permeating ion produces significant electrostatic stabilization of the ion inside the channel. The dielectric self-energy of the ion remains essentially unchanged in the course of the MD simulation, indicating that no substantial changes in the protein geometry occur as the ion passes through it. Also, the model accounts for the experimentally observed saturation of ion current with increase of the electrolyte concentration, in contrast to the predictions of standard PNP theory

The spatial dimension in the development of transport infrastructure in Russian regions

The development of transport infrastructure is a key factor for the economic growth of the whole country and its individual territories. The objectives for the development of transport infrastructure in the regions are determined by the importance of the indicators that have been achieved and are planned, which reflect the transport availability and accessibility of the country’s territories. This article focuses on the development of methodological approaches to assessing the transport availability and accessibility of the territory of the Russian Federation from the perspective of its constituent entities and federal districts based on non-linear coefficients. The authors explain the results of the calculations of the regional dimension in the development of transport infrastructure in Russia based on the Engel and Holz coefficients. The results of the study can be used in further econometric assessments of the influence of various factors on the overall socio-economic development of the regions

Crosslinking constraints and computational models as complementary tools in modeling the extracellular domain of the glycine receptor

The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel superfamily, is the major inhibitory neurotransmitter-gated receptor in the spinal cord and brainstem. In these receptors, the extracellular domain binds agonists, antagonists and various other modulatory ligands that act allosterically to modulate receptor function. The structures of homologous receptors and binding proteins provide templates for modeling of the ligand-binding domain of GlyR, but limitations in sequence homology and structure resolution impact on modeling studies. The determination of distance constraints via chemical crosslinking studies coupled with mass spectrometry can provide additional structural information to aid in model refinement, however it is critical to be able to distinguish between intra- and inter-subunit constraints. In this report we model the structure of GlyBP, a structural and functional homolog of the extracellular domain of human homomeric α1 GlyR. We then show that intra- and intersubunit Lys-Lys crosslinks in trypsinized samples of purified monomeric and oligomeric protein bands from SDS-polyacrylamide gels may be identified and differentiated by MALDI-TOF MS studies of limited resolution. Thus, broadly available MS platforms are capable of providing distance constraints that may be utilized in characterizing large complexes that may be less amenable to NMR and crystallographic studies. Systematic studies of state-dependent chemical crosslinking and mass spectrometric identification of crosslinked sites has the potential to complement computational modeling efforts by providing constraints that can validate and refine allosteric models. © 2014 Liu et al

Types of Higher Education Services Consumption in Russia: Transformation Factors in Focus

The paper briefly describes the composition of socio-technological, socio-managerial, socio-economic, socio-psychological factors that have influenced the change in the motives of purchasing behavior of modern Russians in the market of educational services in the field of higher education. In particular, the major focus is on the introduction of advanced information and communication technologies in the organized educational process. The study also considers (1) the change of conceptual approaches to the organization of the higher education system in favor of practice-oriented learning; (2) the “obsolescence” of the content of educational programs of higher education; (3) the decline in the quality of services offered on the Russian adult education market, and (4) the mismatch of consumer motives in the minds of the family acting as a collective participant in the educational services market. The author’s also present their expert views on the vectors of further development of the market of services in the field of Russian higher education