Analyzing and Biasing Simulations with PLUMED

This chapter discusses how the PLUMED plugin for molecular dynamics can be used to analyze and bias molecular dynamics trajectories. The chapter begins by introducing the notion of a collective variable and by then explaining how the free energy can be computed as a function of one or more collective variables. A number of practical issues mostly around periodic boundary conditions that arise when these types of calculations are performed using PLUMED are then discussed. Later parts of the chapter discuss how PLUMED can be used to perform enhanced sampling simulations that introduce simulation biases or multiple replicas of the system and Monte Carlo exchanges between these replicas. This section is then followed by a discussion on how free-energy surfaces and associated error bars can be extracted from such simulations by using weighted histogram and block averaging techniques

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field

Using metadynamics to explore complex free-energy landscapes

Metadynamics is an atomistic simulation technique that allows, within the same framework, acceleration of rare events and estimation of the free energy of complex molecular systems. It is based on iteratively \u2018filling\u2019 the potential energy of the system by a sum of Gaussians centred along the trajectory followed by a suitably chosen set of collective variables (CVs), thereby forcing the system to migrate from one minimum to the next. The power of metadynamics is demonstrated by the large number of extensions and variants that have been developed. The first scope of this Technical Review is to present a critical comparison of these variants, discussing their advantages and disadvantages. The effectiveness of metadynamics, and that of the numerous alternative methods, is strongly influenced by the choice of the CVs. If an important variable is neglected, the resulting estimate of the free energy is unreliable, and predicted transition mechanisms may be qualitatively wrong. The second scope of this Technical Review is to discuss how the CVs should be selected, how to verify whether the chosen CVs are sufficient or redundant, and how to iteratively improve the CVs using machine learning approaches

Enhanced Conformational Sampling using Replica Exchange with Collective-Variable Tempering

The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. The method is tested on alanine dipeptide and applied to the difficult problem of conformational sampling in a tetranucleotide

Urban household travel behavior in a time of economic crisis: Changes in trip making and transit importance

This research explores changes in trip frequency and importance of bus transit in an urban environment affected by the financial crisis of 2008. The survey was conducted in 2009 in the Reykjavik capital region of Iceland and yielded 1,160 responses. Descriptive analyses and multivariate statistics are applied. The results demonstrate the economic crisis influenced people\u27s travel behavior. About 30% of the participants make fewer trips since the crisis, due in part to reduced income and/or unemployment, suggesting increased risk of transport-related social exclusion. About 20% of the participants perceive bus transit as more important than before, to some extent at the expense of personal automobiles. Important variables associated with reduced trip frequency and increased importance of bus transit were: working more at home and more than 40% household income reduction. Those using their own vehicle less also reported greater bus transit importance. The residents in the suburbs of Reykjavik and in the nearby communities were more likely than the residents in central parts of Reykjavik to reduce their number of trips, suggesting that central city residents were less sensitive to the economic crisis in terms of transportation. The importance of the bus system was found more based on personal and household characteristics than neighborhood type (urban, suburban, nearby communities)

Brain natriuretic peptide is a good predictor for outcome in cardiac surgery

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND AND AIM: The heart secretes brain natriuretic peptide (BNP) in response to myocardial stretch. The aim of this study was to determine whether adverse effects after cardiac surgery were associated with higher serum BNP levels pre-operatively. METHODS: One hundred and thirty-five patients undergoing various cardiac procedures were included in the study, and N-terminal pro-BNP (NT-pro-BNP) was measured pre-operatively. Post-operative complications were defined as follows: (i) a post-operative length of stay in the intensive care unit (ICU) exceeding 48 h; (ii) mortality at 28 days; (iii) the need for inotropic agents and/or intra-aortic balloon pump (IABP); and (iv) renal failure. Serum NT-pro-BNP values were compared for patients with and without complications. The serum NT-pro-BNP level was also correlated with the euroSCORE and ejection fraction (EF). RESULTS: Pre-operative serum NT-pro-BNP levels were significantly higher in patients with an ICU length of stay of more than 2 days or death prior to post-operative day 28 (3118 ng/l vs. 705 ng/l; P < 0.001). Pre-operative serum NT-pro-BNP levels were also significantly higher in patients needing inotropic agents (2628 ng/l vs. 548 ng/l; P < 0.001) or IABP insertion (3705 ng/l vs. 935 ng/l; P = 0.001) or developing renal failure (2857 ng/l vs. 945 ng/l; P < 0.001) post-operatively. The correlation between the serum NT-pro-BNP level and euroSCORE was good (r = 0.658; P < 0.001). The receiver operating characteristic (ROC) curves were used to assess the ability of serum NT-pro-BNP, euroSCORE and EF to predict outcome after cardiac surgery. This revealed an area under the ROC curve for the length of stay in the ICU or mortality at 28 days of 0.829 for serum NT-pro-BNP, 0.814 for euroSCORE and 0.328 for EF assessed by transesophageal echocardiography, indicating that the pre-operative serum NT-pro-BNP level is a good prognostic indicator for outcome after cardiac surgery. CONCLUSION: Serum NT-pro-BNP is a good predictor for complications after cardiac surgery, and is as good as euroSCORE and better than EF

Induced hypothermia in comatose survivors of asphyxia: a case series of 14 consecutive cases

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Induced hypothermia is widely used for comatose survivors of cardiac arrest. Other causes of hypoxic brain injury carry a poor prognosis when treated using traditional methods. At our hospital, hypothermia has also been used for the management of all comatose survivors of asphyxiation. The aim of the present study was to report the results of the management of these patients. METHODS: Hospital charts of all patients admitted unconscious after asphyxiation during a 7-year period were reviewed. This included patients after hanging, drowning, carbon monoxide intoxication and other gas intoxications. In all patients, hypothermia with a target temperature of 32-34 degrees C was induced with external or intravascular cooling for 24 h. The primary outcome was neurologic function at discharge. RESULTS: Fourteen male patients were treated with hypothermia, eight after hanging, three after drowning, two after carbon monoxide intoxication and one after methane intoxication. All were deeply comatose (Glasgow Coma Score 3-5) on arrival to hospital. Nine had been resuscitated from cardiac arrest. There were nine survivors (65%), all with good neurological recovery (Cerebral Performance Category 1-2). Four out of five non-survivors showed cerebral edema already on arrival computed tomographic (CT) scan while none of the nine survivors did. CONCLUSIONS: The results of this study suggest that an early abnormal CT scan of the brain in patients resuscitated after asphyxiation carries an adverse prognosis. The favorable outcome of the patients in the present study suggests that a randomized clinical trial on the use of induced hypothermia in patients exposed to severe asphyxia might be warranted

To Alfred Deakin

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: During the last decade there has been an increased interest in the organisation and quality of trauma care in the Nordic countries. Still, most patients are initially cared for at hospitals with low caseloads of severe trauma. More than 200 hospitals offer initial care to trauma patients. Training of trauma teams using simulators or simulated patients has evolved in the same period, as one important factor to overcome lack of practical training. This overview describes the present state of trauma team training in the Nordic countries. METHODS: Members of a Nordic working group on the use of simulation in medicine reviewed present literature on training with simulation and described the present use of team training in their own countries during winter 2004. RESULTS: There is an increasing amount of evidence indicating that training of teams with simulation reduces treatment errors and improves performance. The training activities do not need to be complex, but skilled debriefing seems necessary. Few Nordic hospitals train their trauma teams. The training activities vary considerably between and within countries. CONCLUSION: There is considerable evidence supporting an increased use of experience gained in other high-risk domains where training in communication, leadership and decision-making is the focus for safety and improvement efforts. There is a need for more widespread training of trauma teams. The different training activities actually undertaken should be scientifically evaluated