4,742 research outputs found
Ligand Discrimination in Myoglobin from Linear-Scaling DFT+U
Myoglobin modulates the binding of diatomic molecules to its heme group via
hydrogen-bonding and steric interactions with neighboring residues, and is an
important benchmark for computational studies of biomolecules. We have
performed calculations on the heme binding site and a significant proportion of
the protein environment (more than 1000 atoms) using linear-scaling density
functional theory and the DFT+U method to correct for self-interaction errors
associated with localized 3d states. We confirm both the hydrogen-bonding
nature of the discrimination effect (3.6 kcal/mol) and assumptions that the
relative strain energy stored in the protein is low (less than 1 kcal/mol). Our
calculations significantly widen the scope for tackling problems in drug design
and enzymology, especially in cases where electron localization, allostery or
long-ranged polarization influence ligand binding and reaction.Comment: 15 pages, 3 figures. Supplementary material 8 pages, 3 figures. This
version matches that accepted for J. Phys. Chem. Lett. on 10th May 201
The genomics of neonatal abstinence syndrome
Significant variability has been observed in the development and severity of neonatal abstinence syndrome (NAS) among neonates exposed to prenatal opioids. Since maternal opioid dose does not appear to correlate directly with neonatal outcome, maternal, placental, and fetal genomic variants may play important roles in NAS. Previous studies in small cohorts have demonstrated associations of variants in maternal and infant genes that encode the ÎĽ-opioid receptor (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero. Consistently falling genomic sequencing costs and computational approaches to predict variant function will permit unbiased discovery of genomic variants and gene pathways associated with differences in maternal and fetal opioid pharmacokinetics and pharmacodynamics and with placental opioid transport and metabolism. Discovery of pathogenic variants should permit better delineation of the risk of developing more severe forms of NAS. This review provides a summary of the current role of genomic factors in the development of NAS and suggests strategies for further genomic discovery
Renormalization of myoglobin-ligand binding energetics by quantum many-body effects
We carry out a first-principles atomistic study of the electronic mechanisms
of ligand binding and discrimination in the myoglobin protein. Electronic
correlation effects are taken into account using one of the most advanced
methods currently available, namely a linear-scaling density functional theory
(DFT) approach wherein the treatment of localized iron 3d electrons is further
refined using dynamical mean-field theory (DMFT). This combination of methods
explicitly accounts for dynamical and multi-reference quantum physics, such as
valence and spin fluctuations, of the 3d electrons, whilst treating a
significant proportion of the protein (more than 1000 atoms) with density
functional theory. The computed electronic structure of the myoglobin complexes
and the nature of the Fe-O2 bonding are validated against experimental
spectroscopic observables. We elucidate and solve a long standing problem
related to the quantum-mechanical description of the respiration process,
namely that DFT calculations predict a strong imbalance between O2 and CO
binding, favoring the latter to an unphysically large extent. We show that the
explicit inclusion of many body-effects induced by the Hund's coupling
mechanism results in the correct prediction of similar binding energies for
oxy- and carbonmonoxymyoglobin.Comment: 7 pages, 5 figures. Accepted for publication in the Proceedings of
the National Academy of Sciences of the United States of America (2014). For
the published article see
http://www.pnas.org/content/early/2014/04/09/1322966111.abstrac
The 2dF gravitational lens survey
The 2 degree Field (2dF) galaxy redshift survey will involve obtaining
approximately 2.5 x 10^5 spectra of objects previously identified as galaxy
candidates on morphological grounds. Included in these spectra should be about
ten gravitationally-lensed quasars, all with low-redshift galaxies as
deflectors (as the more common lenses with high-redshift deflectors will be
rejected from the survey as multiple point-sources). The lenses will appear as
superpositions of galaxy and quasar spectra, and both cross-correlation
techniques and principal components analysis should be able to identify
candidates systematically. With the 2dF survey approximately half-completed it
is now viable to begin a systematic search for these spectroscopic lenses, and
the first steps of this project are described here.Comment: PASA (OzLens edition), in press; 4 pages, 0 figure
A Note on the Use of Mixture Models for Individual Prediction
Mixture models capture heterogeneity in data by decomposing the population into latent subgroups, each of which is governed by its own subgroup-specific set of parameters. Despite the flexibility and widespread use of these models, most applications have focused solely on making inferences for whole or sub-populations, rather than individual cases. The current article presents a general framework for computing marginal and conditional predicted values for individuals using mixture model results. These predicted values can be used to characterize covariate effects, examine the fit of the model for specific individuals, or forecast future observations from previous ones. Two empirical examples are provided to demonstrate the usefulness of individual predicted values in applications of mixture models. The first example examines the relative timing of initiation of substance use using a multiple event process survival mixture model whereas the second example evaluates changes in depressive symptoms over adolescence using a growth mixture model
Subspace confinement : how good is your qubit?
The basic operating element of standard quantum computation is the qubit, an isolated two-level system that can be accurately controlled, initialized and measured. However, the majority of proposed physical architectures for quantum computation are built from systems that contain much more complicated Hilbert space structures. Hence, defining a qubit requires the identification of an appropriate controllable two-dimensional sub-system. This prompts the obvious question of how well a qubit, thus defined, is confined to this subspace, and whether we can experimentally quantify the potential leakage into states outside the qubit subspace. We demonstrate how subspace leakage can be characterized using minimal theoretical assumptions by examining the Fourier spectrum of the oscillation experiment
Development of a Classical Force Field for the Oxidised Si Surface: Application to Hydrophilic Wafer Bonding
We have developed a classical two- and three-body interaction potential to
simulate the hydroxylated, natively oxidised Si surface in contact with water
solutions, based on the combination and extension of the Stillinger-Weber
potential and of a potential originally developed to simulate SiO2 polymorphs.
The potential parameters are chosen to reproduce the structure, charge
distribution, tensile surface stress and interactions with single water
molecules of a natively oxidised Si surface model previously obtained by means
of accurate density functional theory simulations. We have applied the
potential to the case of hydrophilic silicon wafer bonding at room temperature,
revealing maximum room temperature work of adhesion values for natively
oxidised and amorphous silica surfaces of 97 mJ/m2 and 90mJ/m2, respectively,
at a water adsorption coverage of approximately 1 monolayer. The difference
arises from the stronger interaction of the natively oxidised surface with
liquid water, resulting in a higher heat of immersion (203 mJ/m2 vs. 166
mJ/m2), and may be explained in terms of the more pronounced water structuring
close to the surface in alternating layers of larger and smaller density with
respect to the liquid bulk. The computed force-displacement bonding curves may
be a useful input for cohesive zone models where both the topographic details
of the surfaces and the dependence of the attractive force on the initial
surface separation and wetting can be taken into account
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