Exploration of Web Technologies: A Real World Application

Our team created a web application for a photography studio. In addition to a portfolio for the studio, the application required the ability to manage photographer schedules, handle and organize orders and provide secure user accounts with different access levels for the site

Exploring Equilibrium Systems with Nonequilibrium Simulations

Equilibrium sampling is at the core of computational thermodynamics, aiding our understanding of various phenomena in the natural sciences including phase coexistence, molecular solvation, and protein folding. Despite the widespread development of novel sampling strategies over the years, efficient simulation of large complex systems remains a challenge. While the majority of current methods such as simulated tempering, replica exchange, and Monte Carlo methods rely solely on the use of equilibrium techniques, recent results in statistical physics have uncovered the possibility to sample equilibrium states through nonequilibrium simulations. In our first study we present a new replica exchange sampling strategy, "Replica Exchange with Nonequilibrium Switches," which uses nonequilibrium simulations to enhance equilibrium sampling. In our method, trial swap configurations between replicas are generated through nonequilibrium switching simulations which act to drive the replicas towards each other in phase space. By means of these switching simulations we can increase an effective overlap between replicas, enhancing the probability that these moves are accepted and ultimately leading to more effective sampling of the underlying energy landscape. Simulations on model systems reveal that our method can be beneficial in the case of low replica overlap, able to match the efficiency of traditional replica exchange while using fewer processors. We also demonstrate how our method can be applied for the calculation of solvation free energies. In a second, separate study, we investigate the dynamics leading to the dissociation of Na-Cl in water. Here we employ tools of rare event sampling to deduce the role of the surrounding water molecules in promoting the dissociation of the ion pair. We first study the thermodynamic forces leading to dissociation, finding it to be driven energetically and opposed entropically. In further analysis of the system dynamics, we deduce a) the spatial extent over which solvent fluctuations influence dissociation, b) the role of sterics and electrostatics, and c) the importance of inertia in enhancing the reaction probability

Junior Recital, Andrew Ballard, double bass

The presentation of this junior recital will fulfill in part the requirements for the Bachelor of Music degree in Performance. Andrew Ballard studies double bass with Kelly Ali

Superposition-Enhanced Estimation of Optimal Temperature Spacings for Parallel Tempering Simulations.

Effective parallel tempering simulations rely crucially on a properly chosen sequence of temperatures. While it is desirable to achieve a uniform exchange acceptance rate across neighboring replicas, finding a set of temperatures that achieves this end is often a difficult task, in particular for systems undergoing phase transitions. Here we present a method for determination of optimal replica spacings, which is based upon knowledge of local minima in the potential energy landscape. Working within the harmonic superposition approximation, we derive an analytic expression for the parallel tempering acceptance rate as a function of the replica temperatures. For a particular system and a given database of minima, we show how this expression can be used to determine optimal temperatures that achieve a desired uniform acceptance rate. We test our strategy for two atomic clusters that exhibit broken ergodicity, demonstrating that our method achieves uniform acceptance as well as significant efficiency gains.This project was funded by EPSRC Grant EP/I001352/1 and the ERC

Kinetics and mechanism of H/D exchange reactions and racemisation in aqueous solutions: configurational stability of ester and amide arylglycine derivatives

The configurational stability of a range of stereogenic centres in aqueous media has been studied, with the goal of understanding the structural and environmental factors contributing to configurational instability. This information will be of use to the pharmaceutical industry, for which the chiral integrity of drug compounds is imperative. Chapter 1 outlines the background to this project, providing an overview of pharmacological racemisation including potential mechanisms, examples from literature, and the methodology used. Chapter 2 focuses on database mining studies undertaken on AstraZeneca compound libraries, the results of which guided the structures investigated in the rest of the thesis. Most compounds in the libraries do not appear at risk of racemisation. Of those that do, stereogenic centres with proton, carbonyl, aromatic and nitrogen substituents appear most frequently. Chapter 3 discusses experimental work determining rate constants of proton-deuterium exchange (as a model for racemisation) under physiological conditions, for a set of TV-acetyl arylglycine methyl esters. These rate constants suggest that such compounds are susceptible to in vivo racemisation through an SeI mechanism. Chapter 4 outlines experimental work determining rate constants of proton-deuterium exchange, for a set of N-substituted phenylglycine amides. These compounds undergo H/D exchange through an SeI mechanism, although the rate at which H/D exchange occurs suggests they would not be at risk of in vivo racemisation. These results show that an amide substituent is far weaker than a methyl ester in facilitating racemisation. Chapter 5 reports the results of computational studies performed on the compounds investigated in Chapters 3 and 4. The energy gap between a molecule and its anion when deprotonated at the stereogenic centre was correlated with the experimentally determined data, suggesting that prediction of configurational instability for novel compounds may be possible. This correlation only holds when the PCM solvent model is used in calculations

Framing Bias in the Interpretation of Quality Improvement Data: Evidence From an Experiment

Background: A growing body of public management literature sheds light on potential shortcomings to quality improvement (QI) and performance management efforts. These challenges stem from heuristics individuals use when interpreting data. Evidence from studies of citizens suggests that individuals’ evaluation of data is influenced by the linguistic framing or context of that information and may bias the way they use such information for decision-making. This study extends prospect theory into the field of public health QI by utilizing an experimental design to test for equivalency framing effects on how public health professionals interpret common QI indicators.Methods: An experimental design utilizing randomly assigned survey vignettes is used to test for the influence of framing effects in the interpretation of QI data. The web-based survey assigned a national sample of 286 city and county health officers to a “positive frame” group or a “negative frame” group and measured perceptions of organizational performance. The majority of respondents self-report as organizational leadership.Results: Public health managers are indeed susceptible to these framing effects and to a similar degree as citizens. Specifically, they tend to interpret QI information presented in a “positive frame” as indicating a higher level of performance as the same underlying data presenting in a “negative frame.” These results are statistically significant and pass robustness checks when regressed against control variables and alternative sources of information. Conclusion: This study helps identify potential areas of reform within the reporting aspects of QI systems. Specifically, there is a need to fully contextualize data when presenting even to subject matter experts to reduce the existence of bias when making decisions and introduce training in data presentation and basic numeracy prior to fully engaging in QI initiatives

A comparative study of parameterized and full thermal-convection models in the interpretation of heat flow from cratons and mobile belts

Heat flow from Archean cratons worldwide is typically lower than from younger mobile belts surrounding them. The contrast in heat flow between cratons and mobile belts has been attributed in previous studies to the greater thermal resistance of thicker lithosphere beneath the cratons which impedes the flow of mantle heat through the cratons and forces more mantle heat to escape through thinner mobile belt lithosphere. This interpretation is based on thermal models which employ a parameterized convection algorithm to calculate heat transfer in the sublithospheric mantle. We test this interpretation by comparing thermal models constructed using the parameterized convection scheme with models developed using an algorithm for full thermal convection. We show that thermal models constructed using the two different convection algorithms yield similar surface heat flow and thermal structure to moderate depths within the lithosphere. Therefore, we conclude that the interpretation of the heat-flow observations in terms of thicker lithosphere under Archean cratons than under mobile belts is robust in the sense that surface heat flow is not sensitive to the details of heat transfer within the convecting mantle and how deep mantle heat is delivered to the base of the lithosphere.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74756/1/j.1365-246X.1993.tb04665.x.pd

Intrinsically disordered energy landscapes.

Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such 'intrinsically disordered' landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an α-helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.The authors thank Prof. Jane Clarke, Dr. Chris Whittleston, Dr. Joanne Carr, Dr. Iskra Staneva and Dr. David de Sancho for helpful discussions. Y.C. and A.J.B. acknowledge funding from the EPSRC grant number EP/I001352/1, D.C. gratefully acknowledges the Cambridge Commonwealth European and International Trust for financial support and D.J.W. the ERC for an Advanced Grant.This is the final version. It was first published by NPG at http://www.nature.com/srep/2015/150522/srep10386/full/srep10386.html?WT.ec_id=SREP-639%2C638-20150526#abstract