Comment on "Deficiencies in molecular dynamics simulation-based prediction of protein-DNA binding free energy landscapes"

Sequence-specific DNA binding transcription factors play an essential role in the transcriptional regulation of all organisms. The development of reliable in silico methods to predict the binding affinity landscapes of transcription factors thus promises to provide rapid screening of transcription factor specificities and, at the same time, yield valuable insight into the atomistic details of the interactions driving those specificities. Recent literature has reported highly discrepant results on the current ability of state-of-the-art atomistic molecular dynamics simulations to reproduce experimental binding free energy landscapes for transcription factors. Here, we resolve one important discrepancy by noting that in the case of alchemical free energy calculations involving base pair mutations, a common convention used in improving end point convergence of mixed potentials in fact can lead to erroneous results. The underlying cause for inaccurate double free energy difference estimates is specific to the particular implementation of the alchemical transformation protocol. Using the Gromacs simulation package, which is not affected by this issue, we obtain free energy landscapes in agreement with the experimental measurements; equivalent results are obtained for a small set of test cases with a modified version of the AMBER package. Our findings provide a consistent and optimistic outlook on the current state of prediction of protein-DNA binding free energy interactions using molecular dynamics simulations and an important precaution for appropriate end point handling in a broad range of free energy calculations

Client-Driven Advocacy and Psychiatric Disability: A Model for Social Work Practice

This paper presents an innovative advocacy model designed to assist people coping with psychiatric disabilities to fulfill their basic living needs. The model emphasizes the importance of clients defining their own needs for advocacy and then, with the support and assistance of an advocate, taking direct action to fulfill these needs. The model is elaborated in terms of its basic attributes, the interlocking roles of both clients and advocates, the importance of the advocacy relationship, and seven core processes of advocacy. The authors conclude with a discussion of possible effects of introducing the model into social work practice in mental health settings

No Beginning and No End: A Study of the Emergency Room as a Social System

http://deepblue.lib.umich.edu/bitstream/2027.42/50883/1/106.pd

Effects of digital engagement on the quality of life of older people

It is often asserted that older people's quality of life (QOL) is improved when they adopt information and communication technology (ICT) such as the Internet, mobile phones and computers. Similar assumptions are made about older people's use of ICT-based care such as telecare and telehealth. To examine the evidence around these claims, we conducted a scoping review of the academic and grey literature, coving the period between January 2007 and August 2014. A framework analysis approach, based on six domains of QOL derived from the ASCOT and WHOQOL models, was adopted to deductively code and analyse relevant literature. The review revealed mixed results. Older people's use of ICT in both mainstream and care contexts has been shown to have both positive and negative impacts on several aspects of QOL. Studies which have rigorously assessed the impact of older people's use of ICT on their QOL mostly demonstrate little effect. A number of qualitative studies have reported on the positive effects for older people who use ICT such as email or Skype to keep in touch with family and friends. Overall, the review unearthed several inconsistencies around the effects of older people's ICT use on their QOL, suggesting that implicit agreement is needed on the best research methods and instrumentation to adequately describe older people's experiences in today's digital age. Moreover, the available evidence does not consider the large number of older people who do not use ICT and how non-use affects QOL

Going beyond Clustering in MD Trajectory Analysis: An Application to Villin Headpiece Folding

Recent advances in computing technology have enabled microsecond long all-atom molecular dynamics (MD) simulations of biological systems. Methods that can distill the salient features of such large trajectories are now urgently needed. Conventional clustering methods used to analyze MD trajectories suffer from various setbacks, namely (i) they are not data driven, (ii) they are unstable to noise and changes in cut-off parameters such as cluster radius and cluster number, and (iii) they do not reduce the dimensionality of the trajectories, and hence are unsuitable for finding collective coordinates. We advocate the application of principal component analysis (PCA) and a non-metric multidimensional scaling (nMDS) method to reduce MD trajectories and overcome the drawbacks of clustering. To illustrate the superiority of nMDS over other methods in reducing data and reproducing salient features, we analyze three complete villin headpiece folding trajectories. Our analysis suggests that the folding process of the villin headpiece is structurally heterogeneous

Stereochemical errors and their implications for molecular dynamics simulations

<p>Abstract</p> <p>Background</p> <p>Biological molecules are often asymmetric with respect to stereochemistry, and correct stereochemistry is essential to their function. Molecular dynamics simulations of biomolecules have increasingly become an integral part of biophysical research. However, stereochemical errors in biomolecular structures can have a dramatic impact on the results of simulations.</p> <p>Results</p> <p>Here we illustrate the effects that chirality and peptide bond configuration flips may have on the secondary structure of proteins throughout a simulation. We also analyze the most common sources of stereochemical errors in biomolecular structures and present software tools to identify, correct, and prevent stereochemical errors in molecular dynamics simulations of biomolecules.</p> <p>Conclusions</p> <p>Use of the tools presented here should become a standard step in the preparation of biomolecular simulations and in the generation of predicted structural models for proteins and nucleic acids.</p

Two-phase flow analogy as an effective boundary condition for modelling liquids at atomistic resolution

A hybrid Molecular Dynamics/Fluctuating Hydrodynamics framework based on the analogy with two-phase hydrodynamics has been extended to dynamically tracking the feature of interest at all-atom resolution. In the model, the hydrodynamics description is used as an effective boundary condition to close the molecular dynamics solution without resorting to standard periodic boundary conditions. The approach is implemented in a popular Molecular Dynamics package GROMACS and results for two biomolecular systems are reported. A small peptide dialanine and a complete capsid of a virus porcine circovirus 2 in water are considered and shown to reproduce the structural and dynamic properties compared to those obtained in theory, purely atomistic simulations, and experiment

Two center multipole expansion method: application to macromolecular systems

We propose a new theoretical method for the calculation of the interaction energy between macromolecular systems at large distances. The method provides a linear scaling of the computing time with the system size and is considered as an alternative to the well known fast multipole method. Its efficiency, accuracy and applicability to macromolecular systems is analyzed and discussed in detail.Comment: 23 pages, 7 figures, 1 tabl

Unpaid carers of people with dementia and information communication technology: use, impact and ideas for the future

Objectives Several 100,000s of people living with dementia in the UK are cared for at home by a spouse or relative. Few studies have considered the ICT needs and experiences of unpaid carers. This study explores the types of ICT unpaid carers use, the ways they use ICT, the impact of ICT-use, and their ideas for how ICT could be more supportive of their role as a carer. Methods Six focus groups with 32 unpaid carers of people living with dementia discussed their experiences of – and barriers to – using ICT. Transcripts were analysed thematically according to three types of ICT (mainstream, accessible and formal) and five functions (supporting domestic tasks, care management, monitoring, communication and information and education). Results Participants predominantly used mainstream ICT devices such as laptops and smartphones and internet-enabled applications including videoconferencing and social media platforms to support their daily activities and assist them in their caring role. A few participants discussed using accessible devices such as memory clocks and formal telecare and care-phone services for care management and monitoring functions. Participants’ ideas for improvements centred on personalised communication applications that facilitate remote interactions and promote persons living with dementia’s independence. Others expressed concerns about the growing need to use ICT to access formal care services and the inadequacy of the ICT infrastructure in some care homes. Conclusions Unpaid carers mostly turn to readily available mainstream ICT to support their personal and care activities. Further research is required to understand the social impact of the increasing reliance of ICT across health, social and residential care service sectors. Improved cooperation between unpaid carers, technology developers and care services providers could align ICT development to the needs and experiences of families living with dementia and assist unpaid carers with identifying ICTs that optimally support their personal circumstances

Unpaid carers of people with dementia and ICT: use, impact and ideas for the future

Objectives: Several 100,000s of people living with dementia in the UK are cared for at home by a spouse or relative. Few studies have considered the ICT needs and experiences of unpaid carers. This study explores the types of ICT unpaid carers use, the ways they use ICT, the impact of ICT-use, and their ideas for how ICT could be more supportive of their role as a carer. Methods: Six focus groups with 32 unpaid carers of people living with dementia discussed their experiences of – and barriers to – using ICT. Transcripts were analysed thematically according to three types of ICT (mainstream, accessible and formal) and five functions (supporting domestic tasks, care management, monitoring, communication and information and education). Results: Participants predominantly used mainstream ICT devices such as laptops and smartphones and internet-enabled applications including videoconferencing and social media platforms to support their daily activities and assist them in their caring role. A few participants discussed using accessible devices such as memory clocks and formal telecare and care-phone services for care management and monitoring functions. Participants’ ideas for improvements centred on personalised communication applications that facilitate remote interactions and promote persons living with dementia’s independence. Others expressed concerns about the growing need to use ICT to access formal care services and the inadequacy of the ICT infrastructure in some care homes. Conclusions: Unpaid carers mostly turn to readily available mainstream ICT to support their personal and care activities. Further research is required to understand the social impact of the increasing reliance of ICT across health, social and residential care service sectors. Improved cooperation between unpaid carers, technology developers and care services providers could align ICT development to the needs and experiences of families living with dementia and assist unpaid carers with identifying ICTs that optimally support their personal circumstances