Theoretical Studies of Structure-Function Relationships in Kv Channels: Electrostatics of the Voltage Sensor

Voltage-gated ion channels mediate electrical excitability of cellular membranes. Reduced models of the voltage sensor (VS) of Kv channels produce insight into the electrostatic physics underlying the response of the highly positively charged S4 transmembrane domain to changes in membrane potential and other electrostatic parameters. By calculating the partition function computed from the electrostatic energy over translational and/or rotational degrees of freedom, I compute expectations of charge displacement, energetics, probability distributions of translation & rotation and Maxwell stress for arrangements of S4 positively charged residues; these computations can then be compared with experimental results to elucidate the role of various putative atomic level features of the VS. A `paddle' model is rejected on electrostatic grounds, owing to unfavorable energetics, insufficient charge displacement and excessive Maxwell stress. On the other hand, a `sliding helix' model with three local counter-charges, a protein dielectric coefficient of 4 and a 2/3 interval of counter-charge positioning relative to the S4-helix period of positive residues is electrostatically reasonable, comparing well with Shaker (Seoh et al., 1996). Lack of counter-charges destabilizes the S4 in the membrane; counter-charge interval helps determine the number and shape of energy barriers and troughs over the range of motion of the S4; and the local dielectric coefficient of the protein constrains the height of energy maxima. These `sliding helix' models compare favorably with experimental results for single & double mutant charge experiments on Shaker. Single S4 positive charge mutants are predicted quite well by this model; single counter-charge mutants are predicted less well; and double mutants for both an S4 charge and a counter-charge are characterized least well

Voltage sensing in ion channels: Mesoscale simulations of biological devices

Electrical signaling via voltage-gated ion channels depends upon the function of a voltage sensor (VS), identified with the S1-S4 domain in voltage-gated K+ channels. Here we investigate some energetic aspects of the sliding-helix model of the VS using simulations based on VS charges, linear dielectrics and whole-body motion. Model electrostatics in voltage-clamped boundary conditions are solved using a boundary element method. The statistical mechanical consequences of the electrostatic configurational energy are computed to gain insight into the sliding-helix mechanism and to predict experimentally measured ensemble properties such as gating charge displaced by an applied voltage. Those consequences and ensemble properties are investigated for two alternate S4 configurations, \alpha- and 3(10)-helical. Both forms of VS are found to have an inherent electrostatic stability. Maximal charge displacement is limited by geometry, specifically the range of movement where S4 charges and counter-charges overlap in the region of weak dielectric. Charge displacement responds more steeply to voltage in the \alpha-helical than the 3(10)-helical sensor. This difference is due to differences on the order of 0.1 eV in the landscapes of electrostatic energy. As a step toward integrating these VS models into a full-channel model, we include a hypothetical external load in the Hamiltonian of the system and analyze the energetic in/output relation of the VS.Comment: arXiv admin note: substantial text overlap with arXiv:1112.299

Virtual Connectome: Discovering therelationship between structural and functionalconnectivity during steady-states andtransitions

The Virtual Connectome project is a new collaboration between the Charité Universitätsmedizin Berlin, the Indiana University Network Science Institute and the Neuroscience SimLab, JSC, Forschungszentrum Jülich.The main goal of the project is to understand the relationship between structural and functional connectivity in the human brain.Experimental and simulated data of many subjects over long time spans will be analyzed and compared to identify the particular structural connectivity and brain model parameters which better predict the brain activity of the each individual.This presentation aims at providing a general introduction to the project and highlight current work which would benefit from collaborations with mathematicians in order to:1.Understand the capabilities of a Dynamic Mean Field Model of Neural Networks to model transitions between different dynamic states, and refine the model in order to better predict these states.2.Understand the role of the inner inhibition in this Dynamic Mean Field Model in order to obtain a simplified expression which depends on the strength of the inputs to a brain region

Arbor -- a morphologically-detailed neural network simulation library for contemporary high-performance computing architectures

We introduce Arbor, a performance portable library for simulation of large networks of multi-compartment neurons on HPC systems. Arbor is open source software, developed under the auspices of the HBP. The performance portability is by virtue of back-end specific optimizations for x86 multicore, Intel KNL, and NVIDIA GPUs. When coupled with low memory overheads, these optimizations make Arbor an order of magnitude faster than the most widely-used comparable simulation software. The single-node performance can be scaled out to run very large models at extreme scale with efficient weak scaling. HPC, GPU, neuroscience, neuron, softwareComment: PDP 2019 27th Euromicro International Conference on Parallel, Distributed and Network-based Processin

Neutral and Charged Polymers at Interfaces

Chain-like macromolecules (polymers) show characteristic adsorption properties due to their flexibility and internal degrees of freedom, when attracted to surfaces and interfaces. In this review we discuss concepts and features that are relevant to the adsorption of neutral and charged polymers at equilibrium, including the type of polymer/surface interaction, the solvent quality, the characteristics of the surface, and the polymer structure. We pay special attention to the case of charged polymers (polyelectrolytes) that have a special importance due to their water solubility. We present a summary of recent progress in this rapidly evolving field. Because many experimental studies are performed with rather stiff biopolymers, we discuss in detail the case of semi-flexible polymers in addition to flexible ones. We first review the behavior of neutral and charged chains in solution. Then, the adsorption of a single polymer chain is considered. Next, the adsorption and depletion processes in the many-chain case are reviewed. Profiles, changes in the surface tension and polymer surface excess are presented. Mean-field and corrections due to fluctuations and lateral correlations are discussed. The force of interaction between two adsorbed layers, which is important in understanding colloidal stability, is characterized. The behavior of grafted polymers is also reviewed, both for neutral and charged polymer brushes.Comment: a review: 130 pages, 30 ps figures; final form, added reference

Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success