Constant pH molecular dynamics of proteins in explicit solvent with proton tautomerism

pH is a ubiquitous regulator of biological activity, including protein‐folding, protein‐protein interactions, and enzymatic activity. Existing constant pH molecular dynamics (CPHMD) models that were developed to address questions related to the pH‐dependent properties of proteins are largely based on implicit solvent models. However, implicit solvent models are known to underestimate the desolvation energy of buried charged residues, increasing the error associated with predictions that involve internal ionizable residue that are important in processes like hydrogen transport and electron transfer. Furthermore, discrete water and ions cannot be modeled in implicit solvent, which are important in systems like membrane proteins and ion channels. We report on an explicit solvent constant pH molecular dynamics framework based on multi‐site λ‐dynamics (CPHMD MSλD ). In the CPHMD MSλD framework, we performed seamless alchemical transitions between protonation and tautomeric states using multi‐site λ‐dynamics, and designed novel biasing potentials to ensure that the physical end‐states are predominantly sampled. We show that explicit solvent CPHMD MSλD simulations model realistic pH‐dependent properties of proteins such as the Hen‐Egg White Lysozyme (HEWL), binding domain of 2‐oxoglutarate dehydrogenase (BBL) and N‐terminal domain of ribosomal protein L9 (NTL9), and the p K a predictions are in excellent agreement with experimental values, with a RMSE ranging from 0.72 to 0.84 p K a units. With the recent development of the explicit solvent CPHMD MSλD framework for nucleic acids, accurate modeling of pH‐dependent properties of both major class of biomolecules—proteins and nucleic acids is now possible. Proteins 2014; 82:1319–1331. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/1/prot24499-sup-0002-suppinfo02.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/2/prot24499-sup-0001-suppinfo01.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107513/3/prot24499.pd

Many-body Effects in Angle-resolved Photoemission: Quasiparticle Energy and Lifetime of a Mo(110) Surface State

In a high-resolution photoemission study of a Mo(110) surface state various contributions to the measured width and energy of the quasiparticle peak are investigated. Electron-phonon coupling, electron-electron interactions and scattering from defects are all identified mechanisms responsible for the finite lifetime of a valence photo-hole. The electron-phonon induced mass enhancement and rapid change of the photo-hole lifetime near the Fermi level are observed for the first time.Comment: RevTEX, 4 pages, 4 figures, to be published in PR

Local Electronic and Magnetic Structure of Ni below and above TC: A Spin-Resolved Circularly Polarized Resonant Photoemission Study

We report the measurement of the local Ni 3d spin polarization, not only below but also above the Curie temperature (TC), using the newly developed spin-resolved circularly polarized 2p (L3) resonant photoemission technique. The experiment identifies the presence of 3d8 singlets at high energies and 3d8 triplets at low energies extending all the way to the Fermi energy, both below and above TC, showing that it is the orbital degeneracy of the 3d band and the Hund's rule splitting which is of utmost importance to understand Ni and other 3d ferromagnets

Reversible melting and equilibrium phase formation of (Bi,Pb)2Sr2Ca2Cu3O10+d

The decomposition and the reformation of the (Bi,Pb)2Sr2Ca2Cu3O10+d (?Bi,Pb(2223)?) phase have been investigated in-situ by means of High-Temperature Neutron Diffraction, both in sintered bulk samples and in Ag-sheathed monofilamentary tapes. Several decomposition experiments were performed at various temperatures and under various annealing atmospheres, under flowing gas as well as in sealed tubes, in order to study the appropriate conditions for Bi,Pb(2223) formation from the melt. The Bi,Pb(2223) phase was found to melt incongruently into (Ca,Sr)2CuO3, (Sr,Ca)14Cu24O41 and a Pb,Bi-rich liquid phase. Phase reformation after melting was successfully obtained both in bulk samples and Ag-sheathed tapes. The possibility of crystallising the Bi,Pb(2223) phase from the melt was found to be extremely sensitive to the temperature and strongly dependent on the Pb losses. The study of the mass losses due to Pb evaporation was complemented by thermogravimetric analysis which proved that Pb losses are responsible for moving away from equilibrium and therefore hinder the reformation of the Bi,Pb(2223) phase from the melt. Thanks to the full pattern profile refinement, a quantitative phase analysis was carried out as a function of time and temperature and the role of the secondary phases was investigated. Lattice distortions and/or transitions were found to occur at high temperature in Bi,Pb(2223), Bi,Pb(2212), (Ca,Sr)2CuO3 and (Sr,Ca)14Cu24O41, due to cation diffusion and stoichiometry changes. The results indicate that it is possible to form the Bi,Pb(2223) phase from a liquid close to equilibrium conditions, like Bi(2212) and Bi(2201), and open new unexplored perspectives for high-quality Ag-sheathed Bi,Pb(2223) tape processing.Comment: 45 pages (including references,figures and captions), 13 figures Submitted to Supercond. Sci. Techno

Pathotypic diversity of Hyaloperonospora brassicae collected from Brassica oleracea

Downy mildew caused by Hyaloperonospora brassicae is an economically destructive disease of brassica crops in many growing regions throughout the world. Specialised pathogenicity of downy mildews from different Brassica species and closely related ornamental or wild relatives has been described from host range studies. Pathotypic variation amongst Hyaloperonospora brassicae isolates from Brassica oleracea has also been described; however, a standard set of B. oleracea lines that could enable reproducible classification of H. brassicae pathotypes was poorly developed. For this purpose, we examined the use of eight genetically refined host lines derived from our previous collaborative work on downy mildew resistance as a differential set to characterise pathotypes in the European population of H. brassicae. Interaction phenotypes for each combination of isolate and host line were assessed following drop inoculation of cotyledons and a spectrum of seven phenotypes was observed based on the level of sporulation on cotyledons and visible host responses. Two host lines were resistant or moderately resistant to the entire collection of isolates, and another was universally susceptible. Five lines showed differential responses to the H. brassicae isolates. A minimum of six pathotypes and five major effect resistance genes are proposed to explain all of the observed interaction phenotypes. The B. oleracea lines from this study can be useful for monitoring pathotype frequencies in H. brassicae populations in the same or other vegetable growing regions, and to assess the potential durability of disease control from different combinations of the predicted downy mildew resistance genes

Spin-Resolved Photoemission on Anti-Ferromagnets: Direct Observation of Zhang-Rice Singlets in CuO

We demonstrate that it is possible to obtain spin-resolved valence band spectra with a very high degree of spin polarization from antiferromagnetic transition metal materials if the excitation light is circularly polarized and has an energy close to the cation 2p3/2 (L3) white line. We are able to unravel the different spin states in the single-particle excitation spectrum of CuO and show that the top of the valence band is of pure singlet character, which provides strong support for the existence and stability of Zhang-Rice singlets in high-Tc superconductors

Sexuality in the Therapeutic Relationship: An Interpretative Phenomenological Analysis of the Experiences of Gay Therapists

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Gay & Lesbian Mental Health on 17/10/2014 date, available online: DOI: 10.1080/19359705.2014.957882Lesbian, gay, bisexual, transgender, and queer (LGBTQ) clients have reported experiencing heterosexist/homophobic attitudes from heterosexual therapists, but this has seldom been discussed for gay therapists. Such experiences could impact the therapeutic process and a gay therapist’s willingness to self-disclose their sexuality. Self- disclosure of sexuality can be therapeutically beneficial for LGBTQ or heterosexual clients. Semi-structured interviews were conducted with seven gay male therapists and analyzed using Interpretative Phenomenological Analysis. Five themes emerged: affinity for work- ing with LGBTQ clients, heterosexual males’ resistance to the therapeutic process, the impact of homophobia within the therapeu- tic relationship, empathy through shared humanity, and utilizing therapist sexuality as a tool within the therapeutic relationship

Self-energy of image states on copper surfaces

We report extensive calculations of the imaginary part of the electron self-energy in the vicinity of the (100) and (111) surfaces of Cu. The quasiparticle self-energy is computed by going beyond a free-electron description of the metal surface, either within the GW approximation of many-body theory or with inclusion, within the GW$\Gamma$ approximation, of short-range exchange-correlation effects. Calculations of the decay rate of the first three image states on Cu(100) and the first image state on Cu(111) are also reported, and the impact of both band structure and many-body effects on the electron relaxation process is discussed.Comment: 8 pages, 5 figures, to appear in Phys. Rev.

Changes in Muscle Metabolism are Associated with Phenotypic Variability in Golden Retriever Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-chromosome-linked disorder and the most common monogenic disease in people. Affected boys are diagnosed at a young age, become non-ambulatory by their early teens, and succumb to cardiorespiratory failure by their thirties. Despite being a monogenic condition resulting from mutations in the DMD gene, affected boys have noteworthy phenotypic variability. Efforts have identified genetic modifiers that could modify disease progression and be pharmacologic targets. Dogs affected with golden retriever muscular dystrophy (GRMD) have absent dystrophin and demonstrate phenotypic variability at the functional, histopathological, and molecular level. Our laboratory is particularly interested in muscle metabolism changes in dystrophin-deficient muscle. We identified several metabolic alterations, including myofiber type switching from fast (type II) to slow (type I), reduced glycolytic enzyme expression, reduced and morphologically abnormal mitochondria, and differential AMP-kinase phosphorylation (activation) between hypertrophied and wasted muscle. We hypothesize that muscle metabolism changes are, in part, responsible for phenotypic variability in GRMD. Pharmacological therapies aimed at modulating muscle metabolism can be tested in GRMD dogs for efficacy