Understanding thio-effects in simple phosphoryl systems : role of solvent effects and nucleophile charge.

Recent experimental work (J. Org. Chem., 2012, 77, 5829) demonstrated pronounced differences in measured thio-effects for the hydrolysis of (thio)phosphodichloridates by water and hydroxide nucleophiles. In the present work, we have performed detailed quantum chemical calculations of these reactions, with the aim of rationalizing the molecular bases for this discrimination. The calculations highlight the interplay between nucleophile charge and transition state solvation in SN2(P) mechanisms as the basis of these differences, rather than a change in mechanism

Theoretical modelling of epigenetically modified DNA sequences

We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar-phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts

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

Capturing the essence of folding and functions of biomolecules using Coarse-Grained Models

The distances over which biological molecules and their complexes can function range from a few nanometres, in the case of folded structures, to millimetres, for example during chromosome organization. Describing phenomena that cover such diverse length, and also time scales, requires models that capture the underlying physics for the particular length scale of interest. Theoretical ideas, in particular, concepts from polymer physics, have guided the development of coarse-grained models to study folding of DNA, RNA, and proteins. More recently, such models and their variants have been applied to the functions of biological nanomachines. Simulations using coarse-grained models are now poised to address a wide range of problems in biology.Comment: 37 pages, 8 figure

The Alkaline Hydrolysis of Sulfonate Esters: Challenges in Interpreting Experimental and Theoretical Data

Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem. 10, 2012, 8095) presented a nonlinear Brønsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Brønsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data

Market research in the Finnish food industry

This study introduces the important factors of market research and its significancewhen aiming at new foreign markets. Understanding the cultural differences, the consumers and the market itself with the competitors’ actions among other factors, the organization has a better chance to succeed in entering new markets. The case company is a Belgian food industry company which is interested in the Finnish market environment with its consumers and competitors. Currently they are operating in Central European countries with a little market share. An interview was conducted in order to better understand their current situation and expectations on new markets. The company’s products are sold in specialty stores and in bigger hypermarkets due to their higher image which they would like to obtain in Finland. As a small country Finland can not offer big markets but this is no obstacle for the case company since they are not looking to challenge the market leader or even the followers. Instead they are looking for a small market share as in other countries that they already operate in. By using selective distribution focused on the biggest city areas the product availability is guaranteed to the majority of the Finnish population. The thesis emphasizes the different business chains - the different types of stores and their product variety as well as competitors and their product pricing. Among this, the importance of product visibility will be shown as the case company wishes to enter the markets with as little marketing as possible. Regulations on labelling are studied as well as there are little differences from organizations’ home markets. The study also introduces a Finnish importing company that could possibly cooperate with the customer when aiming at the Finnish markets.Tutkimus esittelee markkinatutkimuksen tärkeimmät osa-alueet sekä sen merkityksen tavoiteltaessa uusia markkinoita. Kulttuurillisten eroavaisuuksien, kuluttajien sekä itse markkinoiden ymmärtäminen kilpailijoineen edesauttaa yrityksen menestymistä uudella markkina-alueella. Asiakasyritys on Belgialainen elintarvikeyritys joka kiinnostui Suomen markkinaympäristöstä, kuluttajista sekä kilpailijoista. Tällä hetkellä he toimivat Keski-Euroopan markkinoilla pienin markkinaosuuksin. Haastattelu suoritettiin jotta saataisiin selville heidän nykytilanteensa sekä tulevaisuuden näkymät uusista markkinoista. Yrityksen tuotteet ovat myynnissä erikoisliikkeissä sekä suurimmissa marketeissa korkean imagon vuoksi ja näin he toivoisivat myös tapahtuvan Suomessa. Suomessa ei ole tarjolla suuria markkinoita jo pelkästään maan koon vuoksi. Tämä ei ole kuitenkaan este asiakasyritykselle sillä he eivät lähde haastamaan markkinajohtajaa tai seuraajia, vaan tyytyvät pieneen markkinaosuuteen aivan kuten muillakin markkinoilla. Selektiivisellä tuotejakelulla, keskittyen Suomen suurimpiin kaupunkialueisiin, taataan tuotteiden saatavuus suurimmalle osalle väestöstä. Tutkimus painottuu eri liikeketjuihin, Suomen kauppatyyppeihin ja niiden tuotevalikoiman suuruuteen sekä kilpailijoihin ja heidän tuotehinnoitteluun. Tämän lisäksi tuotteiden näkyvyyden tärkeys osoitetaan, sillä asiakasyritys toivoisi markkinoille tuloa vähäisin markkinointitoiminnoin. Pakkausmerkintäsäännökset tulevat myös esille sillä ne eroavat hieman yrityksen kotimarkkinoiden säännöksistä. Tutkimus esittelee myös suomalaisen maahantuontiyrityksen, joka voisi mahdollisesti toimia asiakasyrityksen yhteistyökumppanina Suomen markkinoille pyrittäessä

Role of Active Site Rigidity in Activity: MD Simulation and Fluorescence Study on a Lipase Mutant

Relationship between stability and activity of enzymes is maintained by underlying conformational flexibility. In thermophilic enzymes, a decrease in flexibility causes low enzyme activity while in less stable proteins such as mesophiles and psychrophiles, an increase in flexibility is associated with enhanced enzyme activity. Recently, we identified a mutant of a lipase whose stability and activity were enhanced simultaneously. In this work, we probed the conformational dynamics of the mutant and the wild type lipase, particularly flexibility of their active site using molecular dynamic simulations and time-resolved fluorescence techniques. In contrast to the earlier observations, our data show that active site of the mutant is more rigid than wild type enzyme. Further investigation suggests that this lipase needs minimal reorganization/flexibility of active site residues during its catalytic cycle. Molecular dynamic simulations suggest that catalytically competent active site geometry of the mutant is relatively more preserved than wild type lipase, which might have led to its higher enzyme activity. Our study implies that widely accepted positive correlation between conformation flexibility and enzyme activity need not be stringent and draws attention to the possibility that high enzyme activity can still be accomplished in a rigid active site and stable protein structures. This finding has a significant implication towards better understanding of involvement of dynamic motions in enzyme catalysis and enzyme engineering through mutations in active site

Combinatorial–computational–chemoinformatics (C3) approach to finding and analyzing low-energy tautomers

Finding the most stable tautomer or a set of low-energy tautomers of molecules is critical in many aspects of molecular modelling or virtual screening experiments. Enumeration of low-energy tautomers of neutral molecules in the gas-phase or typical solvents can be performed by applying available organic chemistry knowledge. This kind of enumeration is implemented in a number of software packages and it is relatively reliable. However, in esoteric cases such as charged molecules in uncommon, non-aqueous solvents there is simply not enough available knowledge to make reliable predictions of low energy tautomers. Over the last few years we have been developing an approach to address the latter problem and we successfully applied it to discover the most stable anionic tautomers of nucleic acid bases that might be involved in the process of DNA damage by low-energy electrons and in charge transfer through DNA. The approach involves three steps: (1) combinatorial generation of a library of tautomers, (2) energy-based screening of the library using electronic structure methods, and (3) analysis of the information generated in step (2). In steps 1–3 we employ combinatorial, computational and chemoinformatics techniques, respectively. Therefore, this hybrid approach is named “Combinatorial*Computational*Chemoinformatics”, or just abbreviated as C3 (or C-cube) approach. This article summarizes our developments and most interesting methodological aspects of the C3 approach. It can serve as an example how to identify the most stable tautomers of molecular systems for which common chemical knowledge had not been sufficient to make definite predictions