GPU-Accelerated Exploration of Biomolecular Energy Landscapes

We present graphics processing unit (GPU)-acceleration of various computational energy landscape methods for biomolecular systems. Basin-hopping global optimization, the doubly nudged elastic band method (DNEB), hybrid eigenvector-following (EF), and a local rigid body framework are described, including details of GPU implementations. We analyze the results for eight different system sizes, and consider the effects of history size for minimization and local rigidification on the overall efficiency. We demonstrate improvement relative to CPU performance of up to 2 orders of magnitude for the largest systems.EPSRC (Grant ID: EP/L504920/1

Designing hierarchical molecular complexity: icosahedra of addressable icosahedra

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Clusters and shells based on icosahedral symmetry are characterised, constructed from component particles that retain memory of their neighbours in a specific reference structure. This memory provides the particles with ‘addressable’ characteristics, with a ground state corresponding to the structure where all the components are correctly addressed in terms of the local environment. The interparticle potentials have separate attractive and repulsive components, defined by the reference structure. For a single target structure, the relaxation efficiency is mostly determined by the variation of the attractive component for correctly and incorrectly addressed particles. The effects of varying the addressability can be visualised directly in terms of the underlying energy landscape, and follow quantitative predictions from catastrophe theory. A doubly-addressable landscape can be designed within the same framework. In well-defined regions of parameter space, the predicted global minima for aggregates of the target cluster (target monomer) form ‘superclusters’, which can be described in terms of multiple interacting copies of local minima for the monomer. The predicted lowest energy superclusters formed from aggregates of addressable icosahedral clusters and shells are themselves based on icosahedral packing. These hierarchical icosahedral structures could be realised experimentally if particles can be synthesised to match the interactions encoded in the addressable potentials.epsr

Exploiting sparsity in free energy basin-hopping

We present acceleration of the vibrational frequency calculations required in free energy basin-hopping (FEBH) global optimisation using sparse Cholesky factorisation. We describe an interface with the SuiteSparse software package that facilitates these calculations, and present results detailing the accuracy and speedups obtained for atomic clusters and biomolecules. For the larger systems, exploiting sparsity reduces the computational cost by factors of ten to thirty, with no significant loss in accuracy. This approach will therefore provide access to the vibrational density of states, and hence to local harmonic free energies, for structure prediction and thermodynamic properties of more complex systems.We gratefully acknowledge funding from the EPSRC (grant references EP/L504920/1 and EP/1001352/1)

Exploring biomolecular energy landscapes

The potential energy landscape perspective provides both a conceptual and a computational framework for predicting, understanding and designing molecular properties. In this Feature Article, we highlight some recent advances that greatly facilitate structure prediction and analysis of global thermodynamics and kinetics in proteins and nucleic acids. The geometry optimisation procedures, on which these calculations are based, can be accelerated significantly using local rigidification of selected degrees of freedom, and through implementations on graphics processing units. Results of progressive local rigidification are first summarised for trpzip1, including a systematic analysis of the heat capacity and rearrangement rates. Benchmarks for all the essential optimisation procedures are then provided for a variety of proteins. Applications are then illustrated from a study of how mutation affects the energy landscape for a coiled-coil protein, and for transitions in helix morphology for a DNA duplex. Both systems exhibit an intrinsically multifunnel landscape, with the potential to act as biomolecular switches.This work was supported by the Engineering and Physical Sciences Research Council (RGM and KR), the Cambridge Commonwealth, European and International Trust (DC), and the Gates Cambridge Trust (JAJ)

The efficacy of high-throughput sequencing and target enrichment on charred archaeobotanical remains

The majority of archaeological plant material is preserved in a charred state. Obtaining reliable ancient DNA data from these remains has presented challenges due to high rates of nucleotide damage, short DNA fragment lengths, low endogenous DNA content and the potential for modern contamination. It has been suggested that high-throughput sequencing (HTS) technologies coupled with DNA enrichment techniques may overcome some of these limitations. Here we report the findings of HTS and target enrichment on four important archaeological crops (barley, grape, maize and rice) performed in three different laboratories, presenting the largest HTS assessment of charred archaeobotanical specimens to date. Rigorous analysis of our data-excluding false-positives due to background contamination or incorrect index assignments-indicated a lack of endogenous DNA in nearly all samples, except for one lightly-charred maize cob. Even with target enrichment, this sample failed to yield adequate data required to address fundamental questions in archaeology and biology. We further reanalysed part of an existing dataset on charred plant material, and found all purported endogenous DNA sequences were likely to be spurious. We suggest these technologies are not suitable for use with charred archaeobotanicals and urge great caution when interpreting data obtained by HTS of these remains

Evaluating the transport, health and economic impacts of new urban cycling infrastructure in Sydney, Australia – protocol paper

BACKGROUND: There are repeated calls to build better cycling paths in Australian cities if the proportion of people cycling is to increase. Yet the full range of transport, health, environmental and economic impacts of new cycling infrastructure and the extent to which observed changes are sustained is not well understood. The City of Sydney is currently building a new bicycle network, which includes a new bicycle path separated from road traffic in the south Sydney area. This protocol paper describes a comprehensive method to evaluate this new cycling infrastructure. METHOD: A cohort of residents within two kilometres of the new bicycle path will be surveyed at baseline before a new section of bicycle path is built, and again 12 and 24 months later to assess changes in travel behaviour, sense of community, quality of life and health behaviours. Residents in a comparable area of Sydney that will not get a new separated bike path will act as a comparison group. At baseline a sub-set of residents who volunteer will also take a small GPS device with them for one week to assess travel behaviour. DISCUSSION: This research should contribute to the advancement in evaluation and appraisal methods for cycling projects

Time-aging time-stress superposition in soft glass under tensile deformation field

We have studied the tensile deformation behaviour of thin films of aging aqueous suspension of Laponite, a model soft glassy material, when subjected to a creep flow field generated by a constant engineering normal stress. Aqueous suspension of Laponite demonstrates aging behaviour wherein it undergoes time dependent enhancement of its elastic modulus as well as its characteristic relaxation time. However, under application of the normal stress, the rate of aging decreases and in the limit of high stress, the aging stops with the suspension now undergoing a plastic deformation. Overall, it is observed that the aging that occurs over short creep times at small normal stresses is same as the aging that occurs over long creep times at large normal stresses. This observation allows us to suggest an aging time - process time - normal stress superposition principle, which can predict rheological behaviour at longer times by carrying out short time tests.Comment: 26 pages, 7 figures, To appear in Rheologica Act

Reminiscence groups for people with dementia and their family carers: pragmatic eight-centre randomised trial of joint reminiscence and maintenance versus usual treatment: a protocol

The growing number of people with dementia, and the increasing cost of care, provides a major incentive to develop and test methods of supporting them in the community for longer. Most attention has been given to pharmacological interventions, but there is increasing recognition that psychosocial interventions may be equally effective, even preferable where medication has negative side-effects. Reminiscence groups, run by professionals and volunteers, which use photographs, recordings and other objects to trigger personal memories are probably the most popular therapeutic approach to working with people with dementia, but there is little evidence for their effectiveness and cost-effectiveness. The recent inclusion of family carers in groups with people with dementia, notably in our own pilot studies, has generated informal evidence that this joint approach improves relationships between people with dementia and their carers, and benefits both

National review of maternity services 2008: women influencing change

<p>Abstract</p> <p>Background</p> <p>In 2009 the Australian government announced a major program of reform with the move to primary maternity care. The reform agenda represents a dramatic change to maternity care provision in a society that has embraced technology across all aspects of life including childbirth.</p> <p>Methods</p> <p>A critical discourse analysis of selected submissions in the consultation process to the national review of maternity services 2008 was undertaken to identify the contributions of individual women, consumer groups and organisations representing the interests of women.</p> <p>Results</p> <p>Findings from this critical discourse analysis revealed extensive similarities between the discourses identified in the submissions with the direction of the 2009 proposed primary maternity care reform agenda. The rise of consumer influence in maternity care policy reflects a changing of the guard as doctors' traditional authority is questioned by strong consumer organisations and informed consumers.</p> <p>Conclusions</p> <p>Unified consumer influence advocating a move away from obstetric -led maternity care for all pregnant women appears to be synergistic with the ethos of corporate governance and a neoliberal approach to maternity service policy. The silent voice of one consumer group (women happy with their obstetric-led care) in the consultation process has inadvertently contributed to a consensus of opinion in support of the reforms in the absence of the counter viewpoint.</p