How conformational changes can affect catalysis, inhibition and drug resistance of enzymes with induced-fit binding mechanism such as the HIV-1 protease

A central question is how the conformational changes of proteins affect their function and the inhibition of this function by drug molecules. Many enzymes change from an open to a closed conformation upon binding of substrate or inhibitor molecules. These conformational changes have been suggested to follow an induced-fit mechanism in which the molecules first bind in the open conformation in those cases where binding in the closed conformation appears to be sterically obstructed such as for the HIV-1 protease. In this article, we present a general model for the catalysis and inhibition of enzymes with induced-fit binding mechanism. We derive general expressions that specify how the overall catalytic rate of the enzymes depends on the rates for binding, for the conformational changes, and for the chemical reaction. Based on these expressions, we analyze the effect of mutations that mainly shift the conformational equilibrium on catalysis and inhibition. If the overall catalytic rate is limited by product unbinding, we find that mutations that destabilize the closed conformation relative to the open conformation increase the catalytic rate in the presence of inhibitors by a factor exp(ddG/RT) where ddG is the mutation-induced shift of the free-energy difference between the conformations. This increase in the catalytic rate due to changes in the conformational equilibrium is independent of the inhibitor molecule and, thus, may help to understand how non-active-site mutations can contribute to the multi-drug-resistance that has been observed for the HIV-1 protease. A comparison to experimental data for the non-active-site mutation L90M of the HIV-1 protease indicates that the mutation slightly destabilizes the closed conformation of the enzyme.Comment: 9 pages, 2 figures, 3 tables; to appear in "BBA Proteins and Proteomics" as part of a special issue with the title "The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

Information theoretic approach for assessing image fidelity in photon-counting arrays

The method of photon-counting integral imaging has been introduced recently for three-dimensional object sensing, visualization, recognition and classification of scenes under photon-starved conditions. This paper presents an information-theoretic model for the photon-counting imaging (PCI) method, thereby providing a rigorous foundation for the merits of PCI in terms of image fidelity. This, in turn, can facilitate our understanding of the demonstrated success of photon-counting integral imaging in compressive imaging and classification. The mutual information between the source and photon-counted images is derived in a Markov random field setting and normalized by the source-image’s entropy, yielding a fidelity metric that is between zero and unity, which respectively corresponds to complete loss of information and full preservation of information. Calculations suggest that the PCI fidelity metric increases with spatial correlation in source image, from which we infer that the PCI method is particularly effective for source images with high spatial correlation; the metric also increases with the reduction in photon-number uncertainty. As an application to the theory, an image-classification problem is considered showing a congruous relationship between the fidelity metric and classifier’s performance

Self-imaging silicon Raman amplifier

We propose a new type of waveguide optical amplifier. The device consists of collinearly propagating pump and amplified Stokes beams with periodic imaging of the Stokes beam due to the Talbot effect. The application of this device as an Image preamplifier for Mid Wave Infrared (MWIR) remote sensing is discussed and its performance is described. Silicon is the preferred material for this application in MWIR due to its excellent transmission properties, high thermal conductivity, high damage threshold and the mature fabrication technology. In these devices, the Raman amplification process also includes four-wave-mixing between various spatial modes of pump and Stokes signals. This phenomenon is unique to nonlinear interactions in multimode waveguides and places a limit on the maximum achievable gain, beyond which the image begins to distort. Another source of image distortion is the preferential amplification of Stokes modes that have the highest overlap with the pump. These effects introduce a tradeoff between the gain and image quality. We show that a possible solution to this trade-off is to restrict the pump into a single higher order waveguide mode.Comment: 11 pages, 5 figures and 5 sections. Submitted to Optics Expres

Real-time Spectroscopy with Sub-GHz Resolution using Amplified Dispersive Fourier Transformation

Dispersive Fourier transformation is a powerful technique in which spectral information is mapped into the time domain using chromatic dispersion. It replaces a spectrometer with an electronic digitizer, and enables real-time spectroscopy. The fundamental problem in this technique is the trade-off between the detection sensitivity and spectral resolution, a limitation set by the digitizer's bandwidth. This predicament is caused by the power loss associated with optical dispersion. We overcome this limitation using Raman amplified spectrum-to-time transformation. An extraordinary loss-less -11.76 ns/nm dispersive device is used to demonstrate single-shot gas absorption spectroscopy with 950 MHz resolution--a record in real-time spectroscopy.Comment: The following article has been accepted by Applied Physics Letter

Amplified Dispersive Fourier-Transform Imaging for Ultrafast Displacement Sensing and Barcode Reading

Dispersive Fourier transformation is a powerful technique in which the spectrum of an optical pulse is mapped into a time-domain waveform using chromatic dispersion. It replaces a diffraction grating and detector array with a dispersive fiber and single photodetector. This simplifies the system and, more importantly, enables fast real-time measurements. Here we describe a novel ultrafast barcode reader and displacement sensor that employs internally-amplified dispersive Fourier transformation. This technique amplifies and simultaneously maps the spectrally encoded barcode into a temporal waveform. It achieves a record acquisition speed of 25 MHz -- four orders of magnitude faster than the current state-of-the-art.Comment: Submitted to a journa

Determination of Aggregate Elastic Properties of Powder-Beds in Additive Manufacturing Using Convolutional Neural Networks

The most popular strategy for the estimation of effective elastic properties of powder-beds in Additively Manufactured structures (AM structures) is through either the Finite Element Method (FEM) or the Discrete Element Method (DEM). Both of these techniques, however, are computationally expensive for practical applications. This paper presents a novel Convolutional Neural Network (CNN) regression approach to estimate the effective elastic properties of powder-beds in AM structures. In this approach, the time-consuming DEM is used for CNN training purposes and not at run time. The DEM is used to model the interactions of powder particles and to evaluate the macro-level continuum-mechanical state variables (volume average of stress and strain). For the Neural Network training purposes, the DEM code creates a dataset, including hundreds of AM structures with their corresponding mechanical properties. The approach utilizes methods from deep learning to train a CNN capable of reducing the computational time needed to predict the effective elastic properties of the aggregate. The saving in computational time could reach 99.9995% compared to DEM, and on average, the difference in predicted effective elastic properties between the DEM code and trained CNN is less than 4%. The resulting sub-second level computational time can be considered as a step towards the development of a near real-time process control system capable of predicting the effective elastic properties of the aggregate at any given stage of the manufacturing process

Periodically-Poled Silicon [Updated]

We propose a new class of photonic devices based on periodic stress fields in silicon that enable second-order nonlinearity as well as quasi-phase matching. Periodically-poled silicon (PePSi) adds the periodic poling capability to silicon photonics, and allows the excellent crystal quality and advanced manufacturing capabilities of silicon to be harnessed for devices based on second-order nonlinear effects. As an example of the utility of the PePSi technology, we present simulations showing that mid-wave infrared radiation can be efficiently generated through difference frequency generation from near-infrared with a conversion efficiency of 50%. This technology can also be implemented with piezoelectric material, which offers the capability to dynamically control the X(2) nonlinearity.Comment: 11 pages, 4 figure

The Dwarf Starburst Host Galaxy of a Type Ia SN at z = 1.55 from CANDELS

We present VLT/X-shooter observations of a high redshift, type Ia supernova host galaxy, discovered with HST/WFC3 as part of the CANDELS Supernova project. The galaxy exhibits strong emission lines of Ly{\alpha}, [O II], H{\beta}, [O III], and H{\alpha} at z = 1.54992(+0.00008-0.00004). From the emission-line fluxes and SED fitting of broad-band photometry we rule out AGN activity and characterize the host galaxy as a young, low mass, metal poor, starburst galaxy with low intrinsic extinction and high Ly{\alpha} escape fraction. The host galaxy stands out in terms of the star formation, stellar mass, and metallicity compared to its lower redshift counterparts, mainly because of its high specific star-formation rate. If valid for a larger sample of high-redshift SN Ia host galaxies, such changes in the host galaxy properties with redshift are of interest because of the potential impact on the use of SN Ia as standard candles in cosmology.Comment: 25 pages, 8 figures. Accepted for publication in Ap