Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods

AbstractBinding of blockers to the human voltage-gated hERG potassium channel is studied using a combination of homology modelling, automated docking calculations and molecular dynamics simulations, where binding affinities are evaluated using the linear interaction energy method. A homology model was constructed based on the available crystal structure of the bacterial KvAP channel and the affinities of a series of sertindole analogues predicted using this model. The calculations reproduce the relative binding affinities of these compounds very well and indicate that both polar interactions near the intracellular opening of the selectivity filter as well as hydrophobic complementarity in the region around F656 are important for blocker binding. These results are consistent with recent alanine scanning mutation experiments on the blocking of the hERG channel by other compounds

Thou Shalt is not You Will

In this paper we discuss some reasons why temporal logic might not be suitable to model real life norms. To show this, we present a novel deontic logic contrary-to-duty/derived permission paradox based on the interaction of obligations, permissions and contrary-to-duty obligations. The paradox is inspired by real life norms

Structure–activity relationship for extracellular block of K+ channels by tetraalkylammonium ions

AbstractExternal tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions

Perhetyön kehittäminen Pohjois-Porin neuvolassa

Tämän opinnäytetyön tarkoituksena oli kehittää perhetyön toimintamalli neuvolatyöskentelyn tueksi hyödyntäen moniammatillista yhteistyötä. Opinnäytetyö toteutettiin kehittämistehtävänä Pohjois-Porin neuvolassa vuosien 2006 ja 2007 aikana. Opinnäytetyö koostui perhetyöntekijän toiminnan ennakkoarvioinnista, toiminnan tarpeen kartoituksesta sekä toiminnan mallittamisesta ja arvioinnista. Tämä opinnäytetyö on osa LAPSOS-hanketta. Opinnäytetyön teoriaosuus koostuu lapsiperheiden voimavarojen sekä yhteiskunnallisen tilanteen tarkastelusta. Teoreettisessa osuudessa tarkastellaan myös neuvolan ja perhetyöntekijän toimintaa sekä moniammatillisen yhteistyön ja ennaltaehkäisevän työn merkitystä lapsiperheiden tukemisessa. Opinnäytetyössä kehittämistehtävän empiirinen osuus toteutettiin toimintatutkimuksena. Aineistot koostuivat teksteistä, kuten kirjallisuudesta ja tutkimuksista sekä fokusryhmän haastatteluista ja kirjallisista muistiinpanoista. Osa aineistosta kerättiin kyselylomakkeella ja tehtävää varten laadittiin kyselylomake. Kerätyt aineistot analysoitiin käyttämällä apuna taulukkolaskentaohjelmaa ja sisällön analyysin menetelmää. Opinnäytetyössä tulokset esitetään kuvioiden ja taulukoiden avulla. Kyselyn keskeinen tulos oli kotikäyntien lisääminen ja sosiaalialan osaamisen tarve Pohjois-Porin neuvolassa. Kyselyn tulosten pohjalta neuvolaan suunniteltiin perhetyön toimintamalli, jota lähdettiin käytännössä kokeilemaan kuuden kuukauden kokeilujakson aikana. Kokeilujakson edetessä toimintaa arvioitiin kolme kertaa ja sitä kehitettiin paremmin neuvolatyöhön sopivaksi. Opinnäytetyön toteuttaminen perustui lapsiperheiden tuentarpeen muuttumiseen ja neuvolatoiminnan kehittämisen tarpeeseen. Opinnäytetyö tuki käytännön toiminnan kehittämistä. Neuvolan perhetyön toimintamalli muotoutuu moniammatillisen yhteistyökokemuksen karttuessa ja tulevaisuudessa toimintamallia voisi kehittää entistä paremmin lapsiperheiden tarpeita vastaavaksi.The purpose of this thesis was to develop an operating model for family work to support child health clinic services and utilize multiprofessional cooperation. The research was conducted as a development project in the Northern Pori Child Health Clinic during 2006 and 2007. The study consisted of pre-evaluation, needs analysis, modelling, and evaluation of family workers’ actions. This thesis is a part of project called LAPSOS. In the theoretical part of the study, the resources of families with children and their social situations were examined. In this same context, the services of the Child Health Clinic and actions of the family worker were studied and the importance of pre-emptive actions in supporting families was determined. In this thesis, the empirical part of the development project was implemented as action research. The study data consisted of text references, such as literature and previous research in the field, as well as focus group interviews and written notes. Some of the data was gathered with a questionnaire, which was specially designed for this task. The data was analysed by using spreadsheets and content analysis method and the results are presented as charts and tables. The key result of this survey was to increase health visits. The Northern Pori Child Health Clinic also needed more expertise in the field of social services. An operating model for family work was designed on the basis of these results. The model was implemented in practice as a pilot project for a period of six months. As the pilot project progressed, its functionality was evaluated three times. In addition, the project was further developed to meet the child health clinic needs. This thesis was based on the changing needs of families and the demand for the development of child health clinic activities. It also supported the development of practical work. The Child Health Clinic operating model for family work will find its shape as multiprofessional cooperation increases. In the future, the operating model could be further developed to better meet the families’ needs

Meningkatkan Kinerja Database Billing pada Warnet PT. Dinustech dengan Menggunakan Trigger dan Stored Procedure

Laporan Tugas Akhir dengan judul "Meningkatkan Kinerja Database Billing Pada Warnet PT. Dinustech dengan Menggunakan Trigger dan Stored Procedure" merupakan sistem yang di buat untuk memperbaiki sistem yang sudah ada dalam database billing. Sistem yang dibuat ini diharapkan dapat meningkatkan kinerja database billing sehingga mengurangi delay atau lag pada sistem sebelumnya Metodologi pengumpulan data menggunakan metode : interview yaitu cara mengumpulkan data dengan mengadakan tanya jawab langsung dengan bagian yang berhubungan dengan obyek yang diteliti. Survei yaitu pengamatan langsung mengenai sistem database yang lama pada Warnet PT. Dinustec. Studi pustaka adalah pengumpulan data dengan mempelajari buku atau literatur-literatur mengenai perancangan dan desain suatu sistem. Desain sistem dan perancangan database yang digunakan mulai dari Context Diagram, DFD Level, ERD, Normalisasi dan Kamus Data menghasilkan suatu sistem database yang lebih baik dan tertata dibandingkan dengan database sebelumnya, Peningkatan pada sistem database ini terdapat pada penataan ulang relasi-relasi tabel pada database sebelumnya. Kemudian melakukan otomatisasi pada beberapa proses dengan menggunakan trigger dan stored procedure. Dengan adanya peningkatan ini, masalah-masalah sebelumnya berupa delay atau lag pada client warnet tersebut berkurang, dan juga sistem laporan pun menjadi lebih mudah dan jelas

Calculation of absolute free energy of binding for theophylline and its analogs to RNA aptamer using nonequilibrium work values

The massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) has been developed [H. Fujitani, Y. Tanida, M. Ito, G. Jayachandran, C. D. Snow, M. R. Shirts, E. J. Sorin, and V. S. Pande, J. Chem. Phys. ${\bf 123}$, 084108 (2005)]. As an application, we perform the binding affinity calculations of six theophylline-related ligands with RNA aptamer. Basically, our method is applicable when using many compute nodes to accelerate simulations, thus a parallel computing system is also developed. To further reduce the computational cost, the adequate non-uniform intervals of coupling constant $\lambda$, connecting two equilibrium states, namely bound and unbound, are determined. The absolute binding energies $\Delta G$ thus obtained have effective linear relation between the computed and experimental values. If the results of two other different methods are compared, thermodynamic integration (TI) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) by the paper of Gouda $et al$ [H. Gouda, I. D. Kuntz, D. A. Case, and P. A. Kollman, Biopolymers ${\bf 68}$, 16 (2003)], the predictive accuracy of the relative values $\Delta\Delta G$ is almost comparable to that of TI: the correlation coefficients (R) obtained are 0.99 (this work), 0.97 (TI), and 0.78 (MM-PBSA). On absolute binding energies meanwhile, a constant energy shift of $\sim$ -7 kcal/mol against the experimental values is evident. To solve this problem, several presumable reasons are investigated.Comment: 23 pages including 6 figure

O(N) continuous electrostatics solvation energies calculation method for biomolecules simulations

We report a development of a new fast surface-based method for numerical calculations of solvation energy of biomolecules with a large number of charged groups. The procedure scales linearly with the system size both in time and memory requirements, is only a few percent wrong for any molecular configurations of arbitrary sizes, gives explicit value for the reaction field potential at any point, provides both the solvation energy and its derivatives suitable for Molecular Dynamics simulations. The method works well both for large and small molecules and thus gives stable energy differences for quantities such as solvation energies of molecular complex formation.Comment: 6 pages, 4 figures, more results, examples and references adde

Exploring Spirituality in Teaching Within a Christian School Context Through Collaborative Action Research

This article reports on a collaborative action research project conducted in New Zealand, during 2012, exploring spirituality in teaching within a Christian school context. The experienced primary school teacher participant chose to take action around the issue of personal fear and insecurity which were believed to be hindering professional growth and relationships. Through self-directed inquiry, critical reflective journaling, Bible study, fellowship and prayer with trusted friends, the teacher experienced a renewed sense of peace and freedom in Christ. This personal transformation was believed to be influential on subsequent professional practice, assisting the teacher to become more relational, responsive and compassionate. The findings provide a rich description of the participant’s spirituality, the lived reality of a person’s spiritual life. This report will be of interest to teachers, teacher-leaders and teacher-educators who desire to explore Christian spirituality through practitioner-led inquiry