Advances in biomedical research require a new generation of researchers having a strong background in both the life and physical sciences and a knowledge of computational, mathematical, and ...engineering tools for tackling biological problems. The NIH‐NSF Bioengineering and Bioinformatics Summer Institute at the University of Pittsburgh (BBSI @ Pitt;www.ccbb.pitt.edu/bbsi) is a multi‐institutional 10‐week summer program hosted by the University of Pittsburgh, Duquesne University, the Pittsburgh Supercomputing Center, and Carnegie Mellon University, and is one of nine Institutes throughout the nation currently participating in the NIH‐NSF program. Each BBSI focuses on a different area; the BBSI @ Pitt, entitled “Simulation and Computer Visualization of Biological Systems at Multiple Scales”, focuses on computational and mathematical approaches to understanding the complex machinery of molecular‐to‐cellular systems at three levels, namely, molecular, subcellular (microphysiological), and cellular. We present here an overview of the BBSI@Pitt, the objectives and focus of the program, and a description of the didactic training activities that distinguish it from other traditional summer research programs. Furthermore, we also report several challenges that have been identified in implementing such an interdisciplinary program that brings together students from diverse academic programs for a limited period of time. These challenges notwithstanding, presenting an integrative view of molecular‐to‐system analytical models has introduced these students to the field of computational biology and has allowed them to make an informed decision regarding their future career prospects.
The voltage-dependent anion channel (VDAC) is the major pathway mediating the transfer of metabolites and ions across the mitochondrial outer membrane. Two hallmarks of the channel in the open state ...are high metabolite flux and anion selectivity, while the partially closed state blocks metabolites and is cation selective. Here we report the results from electrostatics calculations carried out on the recently determined high-resolution structure of murine VDAC1 (mVDAC1). Poisson–Boltzmann calculations show that the ion transfer free energy through the channel is favorable for anions, suggesting that mVDAC1 represents the open state. This claim is buttressed by Poisson–Nernst–Planck calculations that predict a high single-channel conductance indicative of the open state and an anion selectivity of 1.75—nearly a twofold selectivity for anions over cations. These calculations were repeated on mutant channels and gave selectivity changes in accord with experimental observations. We were then able to engineer an in silico mutant channel with three point mutations that converted mVDAC1 into a channel with a preference for cations. Finally, we investigated two proposals for how the channel gates between the open and the closed state. Both models involve the movement of the N-terminal helix, but neither motion produced the observed voltage sensitivity, nor did either model result in a cation-selective channel, which is observed experimentally. Thus, we were able to rule out certain models for channel gating, but the true motion has yet to be determined.
Abstract only
Background
Claudin‐2 is a paracellular channel. Na and water flow through it driven by an osmotic or Na concentration gradient, suggesting that Na and water pass through a common pore ...and that their fluxes are frictionally coupled. We investigated the mechanism by molecular dynamics simulations.
Methods
The claudin pore was modeled either as a double cone or a cylindrical nanotube with narrowest diameter of 6.5 Å and 6 negatively charged sites in the middle of the pore (each ‐0.2e). A hydrostatic pressure gradient was applied via an additional constant force in the channel axis direction to a layer of water molecules parallel to the membrane interface. Simulations were performed using the CHARMM27 force field and the TIP3P water model, with full electrostatics was included.
Results
With an osmotic gradient, water molecules oriented within the pore in 2 water wires and exhibited directional flow with Pf= 4.7 x 10‐13 cm
3
/s and a water:Na flux ratio of 233. Increasing the magnitude of the negative charge increased permeability only when the charges were smeared evenly along the pore surface. Application of a Na concentration gradient, also drove water flow with water:Na flux of 14.6. Increasing the pore diameter to 7Å also increased water flow significantly by allowing 3 water wires to form.
Conclusions
Our findings confirm that water can permeate through claudin‐2 via a water wire mechanism, demonstrate that water permeability is dependent on the magnitude and distribution of intrapore charges and on the pore diameter, and provide a molecular explanation for the frictional coupling of Na and water fluxes within the pore.
A random-walk simulation of microdialysis is used to examine how a reaction that consumes analyte in the medium external to the probe affects the extraction and recovery processes. The simulations ...suggest that such a reaction can promote the extraction process while simultaneously inhibiting the recovery process, which appears to be consistent with recent experimental evidence of asymmetry in the extraction and recovery of the neurotransmitter, dopamine, during brain microdialysis. This suggests that quantitative microdialysis strategies that rely on the extraction fraction as a measure of the probe recovery value, such as the no-net-flux method, will produce an underestimate of the analyte concentration in the external medium when that analyte is consumed by a reaction in the external medium. Furthermore, if experimental conditions arise under which the kinetics of the reaction are changed, then changes in the extraction and recovery processes are likely to occur as well. The implications of these theoretical findings for the quantitative interpretation of in vivo microdialysis results obtained for the neurotransmitter dopamine are examined.
Lattice-field calculations are performed on a Gaussian polymer chain confined to move within the region defined by two fused spheres. The results of the calculations are in accord with recent ...experimental measurements and computer simulations, and suggest that current theoretical understanding of polymer partitioning phenomena is inadequate when excluded volume interactions between the monomers are present. It is also shown that the notion of ground state dominance can fail even in the large monomer limit.
Diffraction in crystalline colloidal-array photonic crystals Asher, Sanford A; Weissman, Jesse M; Tikhonov, Alexander ...
Physical review. E, Statistical, nonlinear, and soft matter physics,
06/2004, Letnik:
69, Številka:
6 Pt 2
Journal Article
We characterized the diffraction and crystal structure of a crystalline colloidal array (CCA) photonic crystal composed of 270 nm diameter polystyrene spheres which have a nearest neighbor spacing of ...approximately 540 nm. This CCA diffracts light in first order at approximately 1200 nm and shows strong diffraction in the visible spectral region from higher order planes. We quantitatively examined the relative diffraction intensities of the putative fcc (111), (200), (220), and (311) planes. Comparing these intensities to those calculated theoretically we find that the crystal structure is fcc with significant stacking faults. Essentially, no light transmits at the Bragg angle for the fcc (111) planes even through thin approximately 40 microm thick CCA. However, much of this light is diffusely scattered about the Bragg angle due to crystal imperfections. Significant transmission occurs from thin samples oriented at the Bragg condition for the fcc (200), (220), and (311) planes. We also observe moderately intense two-dimensional diffraction from the first few layers at the crystal surfaces. We also examined the sample thickness dependence of diffraction from CCA photonic crystals prepared from approximately 120 nm polystyrene spheres whose fcc (111) planes diffract in the visible spectral region. These experimental observations, aided by calculations based upon a simple but flexible model of light scattering from an arbitrary collection of colloidal spheres, make clear that fabrication of three-dimensional photonic band gap crystals will be challenged by crystal imperfections.
We theoretically characterized the diffraction properties of both closed-packed and non-closed-packed crystalline colloidal array (CCA) photonic crystals. A general theory based on single-scattering ...kinematic approach was developed and used to calculate the diffraction efficiency of CCA of different sphere diameters at different incident light angles. Our theory explicitly relates the scattering properties of individual spheres (calculated by using Mie theory) comprising a CCA to the CCA diffraction efficiency. For a CCA with a lattice constant of 380 nm, we calculated the relative diffraction intensities of the fcc (111), (200), and (220) planes and determined which sphere diameter gives rise to the most efficiently diffracting CCA for each set of crystal planes. The effective penetration depth of the light was calculated for several crystal planes of several CCAs of different sphere diameters at different angles of incidence. The typical penetration depth for a CCA comprised of polystyrene spheres was calculated to be in the range of 10-40 CCA layers. A one-dimensional (1D) model of diffraction from the stack of (111) fcc crystal layers was developed and used to assess the role of multiple scattering and to test our single-scattering approach. The role of disorder was studied by using this 1D scattering model. Our methodology will be useful for the optimization of photonic crystal coating materials.
Many semiclassical wave packet propagation methods require only local potential energy surface information in order to update a Gaussian wave packet over a short time interval. These data, which ...include the evaluation of the potential energy at the instantaneous configuration space center of the wave packet, plus the gradient vector and Hessian (second derivative) matrix at the same configuration, can be generated efficiently by extant electronic structure packages. This leads to an algorithm for propagating semiclassical Gaussian wave packets using electronic structure data computed “on the fly” in the course of the propagation. The feasibility of such a strategy for condensed phase systems is demonstrated by using it (with an appropriate approximate level of electronic structure theory) to calculate Franck−Condon absorption and emission spectra of all-trans 1,3,5,7-octatetraene in the gas phase, and in both chloroform and methanol solvents. Good agreement with the corresponding experimentally measured spectra is obtained.
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