Simulation of pH-Dependent Conformational Transitions in Membrane Proteins: The CLC-ec1 Cl−/H+ Antiporter

Intracellular transport of chloride by members of the CLC transporter family involves a coupled exchange between a Cl⁻ anion and a proton (H⁺), which makes the transport function dependent on ambient pH. Transport activity peaks at pH 4.5 and stalls at neutral pH. However, a structure of the WT protein at acidic pH is not available, making it difficult to assess the global conformational rearrangements that support a pH-dependent gating mechanism. To enable modeling of the CLC-ec1 dimer at acidic pH, we have applied molecular dynamics simulations (MD) featuring a new force field modification scheme—termed an Equilibrium constant pH approach (ECpH). The ECpH method utilizes linear interpolation between the force field parameters of protonated and deprotonated states of titratable residues to achieve a representation of pH-dependence in a narrow range of physiological pH values. Simulations of the CLC-ec1 dimer at neutral and acidic pH comparing ECpH-MD to canonical MD, in which the pH-dependent protonation is represented by a binary scheme, substantiates the better agreement of the conformational changes and the final model with experimental data from NMR, cross-link and AFM studies, and reveals structural elements that support the gate-opening at pH 4.5, including the key glutamates Glu_in and Glu_ex.     

Dynamic models of G-protein coupled receptor dimers: indications of asymmetry in the rhodopsin dimer from molecular dynamics simulations in a POPC bilayer

Based on the growing evidence that G-protein coupled receptors (GPCRs) form homo- and hetero-oligomers, models of GPCR signaling are now considering macromolecular assemblies rather than monomers, with the homo-dimer regarded as the minimal oligomeric arrangement required for functional coupling to the G-protein. The dynamic mechanisms of such signaling assemblies are unknown. To gain some insight into properties of GPCR dimers that may be relevant to functional mechanisms, we study their current structural prototype, rhodopsin. We have carried out nanosecond time-scale molecular dynamics (MD) simulations of a rhodopsin dimer and compared the results to the monomer simulated in the same type of bilayer membrane model composed of an equilibrated unit cell of hydrated palmitoyl-oleoyl-phosphatidyl choline (POPC). The dynamic representation of the homo-dimer reveals the location of structural changes in several regions of the monomeric subunits. These changes appear to be more pronounced at the dimerization interface that had been shown to be involved in the activation process [Proc Natl Acad Sci USA 102:17495, 2005]. The results are consistent with a model of GPCR activation that involves allosteric modulation through a single GPCR subunit per dimer.     

Efficient broadband silicon-on-insulator grating coupler with low backreflection

We design and fabricate an efficient broadband grating coupler on a 400 nm thick silicon-on-insulator wafer. The measured coupling loss is 3 dB when coupling to a single-mode fiber at 1310 nm wavelength with TE polarization. The spectral FWHM and backreflection are determined to be 58 nm and -27 dB, respectively.     

Order statistics applications to queueing and scheduling problems

We prove several basic combinatorial identities and use them in two applications: the queue inference engine (QIE) and earliest due date rule (EDD) scheduling. Larson (1990) introduced the QIE. His objective was to deduce the behavior of a multiserver queueing system without observing the queue. With only a Poisson arrival assumption, he analyzed the performance during a busy period. Such a period starts once all servers are busy with the queue empty, and it ends as soon as a server becomes idle. We generalize the standard order statistics result for Poisson processes, and show how to sample a busy period in the M/M/c system. We derive simple expressions for the variance of the total waiting time in the M/M/c and M/D/1 queues given that n Poisson arrivals and departures occur during a busy period. We also perform a probabilistic analysis of the EDD for a one-machine scheduling problem with earliness and tardiness penalties. The schedule is without preemption and with no inserted idle time. The jobs are independent and each may have a different due date. For large n, we show that the variance of the total penalty costs of the EDD is linear in n. The mean of the total penalty costs of the EDD is known to be proportional to the square root of n (see Harel (1993)). This revised version was published online in June 2006 with corrections to the Cover Date.     

Implementation of a CNOT gate in two cold Rydberg atoms by the nonholonomic control technique

We present a demonstrative application of the nonholonomic control method to a real physical system composed of two cold Cesium atoms. In particular, we show how to implement a CNOT quantum gate in this system by means of a controlled Stark field.     

Thermal‐crosslinked polyacrylonitrile fiber compacts

Polyacrylonitrile (PAN) textile fibers, in the form of fabrics or threads, were compacted in a heat‐pressure cycle and crosslinked by nitrile polymerization to form a thermoset composite article, whose mechanical properties were found to surpass those of commercially available polypropylene (PP) fiber counterparts. Additional advantages of the PAN compacts included their significant thermal stability (>300°C, i.e., twice that of PP) in addition to their flame retardancy, thereby rendering them as the structural material of choice for applications where heat protection and fire resistance are essential. Copyright © 2009 John Wiley & Sons, Ltd.     

Synchrotron radiation of crystallized beams

We study the modifications of synchrotron radiation of charges in a storage ring as they are cooled. The pair correlation lengths between the charges are manifest in the synchrotron radiation and coherence effects exist for wavelengths longer than the coherence lengths between the charges. Therefore, the synchrotron radiation can be used as a diagnostic tool to determine the state (gas, liquid, crystal) of the charged plasma in the storage ring. We show also that the total power of the synchrotron radiation is significantly reduced for crystallized beams, both coasting and bunched. This opens the possibility of accelerating particles to ultrarelativistic energies using small-sized cyclic accelerators.     

Law of the iterated logarithm for perturbed empirical distribution functions evaluated at a random point for nonstationary random variables

We consider perturbed empirical distribution functions , where {Ginn, n1} is a sequence of continuous distribution functions converging weakly to the distribution function of unit mass at 0, and {X _{i, i}1} is a non-stationary sequence of absolutely regular random variables. We derive the almost sure representation and the law of the iterated logarithm for the statistic whereU _n is aU-statistic based onX ₁,...,X _n . The results obtained extend or generalize the results of Nadaraya,⁽⁷⁾ Winter,⁽¹⁶⁾ Puri and Ralescu,^(9,10) Oodaira and Yoshihara,⁽⁸⁾ and Yoshihara,⁽¹⁹⁾ among others.Research supported by the Office of Naval Research Contract N00014-91-J-1020.     

Brownian dynamics simulations of the reactions of hydrated electrons with components of DNAs and a DNA double-helix

As a first step toward developing simulation models for studying the indirect mechanism of radiation damage to DNAs, we have carried out Brownian dynamics simulations to study the reactions of hydrated electrons with a 12-base-pair B-DNA, (dA)₁₂(dT)₁₂, and with bases, monodeoxynucleotides, and polydeoxynucleotides. We first studied in detail the sensitivity of diffusion reaction rate constants to different model and simulation parameters. Based on the sensitivity studies, a set of model and simulation parameters was obtained for the final production runs. The use of this set of parameters reduced the computational costs but delivered reasonably reliable results. The calculated reaction rate constants were in qualitative agreement with experiments. For the DNA double-helix, (dA)₁₂(dT)₁₂, the simulations demonstrated that hydrated electrons preferred to attack the two ends of the double-helix. Electrostatic interactions between the DNA and the hydrated electrons make the T strand more susceptible to attack than the A strand. The increased reactivity of the T strand due to electrostatic interactions results from the increased reactivity of the C6 sites of the thymine bases, at the expense of the reactivity of the C8 sites of the adenine bases. The reactivity of the relatively buried reactive sites of the adenine and thymine bases are less affected by electrostatic interactions. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 888–901, 1997