Exploiting molecular dynamics in Nested Sampling simulations of small peptides

Nested Sampling (NS) is a parameter space sampling algorithm which can be used for sampling the equilibrium thermodynamics of atomistic systems. NS has previously been used to explore the potential energy surface of a coarse-grained protein model and has significantly outperformed parallel tempering when calculating heat capacity curves of Lennard-Jones clusters. The original NS algorithm uses Monte Carlo (MC) moves; however, a variant, Galilean NS, has recently been introduced which allows NS to be incorporated into a molecular dynamics framework, so NS can be used for systems which lack efficient prescribed MC moves. In this work we demonstrate the applicability of Galilean NS to atomistic systems. We present an implementation of Galilean NS using the Amber molecular dynamics package and demonstrate its viability by sampling alanine dipeptide, both in vacuo and implicit solvent. Unlike previous studies of this system, we present the heat capacity curves of alanine dipeptide, whose calculation provides a stringent test for sampling algorithms. We also compare our results with those calculated using replica exchange molecular dynamics (REMD) and find good agreement. We show the computational effort required for accurate heat capacity estimation for small peptides. We also calculate the alanine dipeptide Ramachandran free energy surface for a range of temperatures and use it to compare the results using the latest Amber force field with previous theoretical and experimental results.We acknowledge support from the Leverhulme Trust (Grant F/00 215/BL(NSB, CV and DLW)) and the EPSRC (Grants EP/J020281/1(DLW), EP/J010847/1 (GC) and a Doctoral Training Award (RJB)).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.cpc.2015.12.00

Targeted modulation of tropoelastin structure and assembly

Tropoelastin, as the monomer unit of elastin, assembles into elastic fibers that impart strength and resilience to elastic tissues. Tropoelastin is also widely used to manufacture versatile materials with specific mechanical and biological properties. The assembly of tropoelastin into elastic fibers or biomaterials is crucially influenced by key submolecular regions and specific residues within these domains. In this work, we identify the functional contributions of two rarely occurring negatively charged residues, glutamate 345 in domain 19 and glutamate 414 in domain 21, in jointly maintaining the native conformation of the tropoelastin hinge, bridge and foot regions. Alanine substitution of E345 and/or E414 variably alters the positioning and interactive accessibility of these regions, as illustrated by nanostructural studies and detected by antibody and cell probes. These structural changes are associated with a lower propensity for monomer coacervation, cross-linking into morphologically and functionally atypical hydrogels, and markedly impaired and abnormal elastic fiber formation. Our work indicates the crucial significance of both E345 and E414 residues in modulating specific local structure and higher-order assembly of human tropoelastin

Look Who\u27s Talking: Differences in Rates of Interruptions and Proportion of Time Used by Male and Female U.S. Courts of Appeals Judges

During oral arguments, attorneys are given the chance to elaborate on their written briefs and answer questions from the judges deciding the case. Studying oral arguments can be a window into the power dynamics between judges and attorneys, and can shed light onto how factors like gender may affect judicial decision-making. While a growing body of research has examined gender dynamics in oral arguments in the United States Supreme Court, no existing studies have examined whether these findings hold up in the U.S. Court of Appeals, the second highest courts in the country. We collected data on two years of oral arguments from the 4th Circuit in order to test theories about gender and speech patterns, including interruptions and verbosity

Electrospray and Photoionization Mass Spectrometry for the Characterization of Organic matter in Natural Waters: A Qualitative Assessment

Fourier-transform ion cyclotron resonance mass spectrometry (MS) has demonstrated potential to revolutionize the fields of limnology and chemical oceanography by identifying the individual molecular components of organic matter in natural waters. The use of MS for this purpose is made possible by the electrospray technique which successfully ionizes polar, nonvolatile organic molecules. Another recently developed ion source, atmospheric pressure photoionization (APPI), extends MS capabilities to less polar molecules. This article presents early results on the application of APPI MS to natural organic matter. We compare APPI MS and electrospray MS data for dissolved organic matter from Lake Drummond (Virginia, USA). Collectively, electrospray and APPI MS identify more than 6000 molecular species to which we assign unique molecular formulas. Fewer than 1000 molecular species are common to both electrospray and APPI mass spectra, indicating that the techniques are highly complementary in the types of molecules they ionize. Access to a broad range of molecules provided by combining APPI and electrospray has prompted a qualitative analysis. The goal is to assess the extent to which molecular MS data correspond with elemental (CHNOS) and structural characteristics determined by combustion elemental analyses and 13C nuclear magnetic resonance (NMR). Because the data obtained by these different methods are not directly comparable, we propose a novel data analysis procedure that facilitates their comparison. The bulk elemental composition calculated from electrospray MS data are in close agreement (±15%) with values determined by combustion elemental analysis. APPI and electrospray MS detect protein contributions in agreement with 13C NMR (6 wt %) but underestimate carbohydrates relative to 13C NMR. Nevertheless, MS results agree with NMR on the relative proportions of noncarbohydrate compounds in the organic matter: lignins \u3e lipids \u3e peptides. Finally, we use a molecular mixing model to simulate a 13C NMR spectrum from the MS datasets. The correspondence of the simulated and measured 13C NMR signals (74%) suggests that, collectively, the molecular species identified by APPI and electrospray MS comprise a large portion of the organic matter in Lake Drummond. These results add credibility to electrospray and APPI MS in limnology and oceanography applications, but further characterization of ion source behavior is fundamental to the accurate interpretation of MS data

Management and drivers of change of pollinating insects and pollination services. National Pollinator Strategy: for bees and other pollinators in England, Evidence statements and Summary of Evidence

These Evidence Statements provide up-to-date information on what is known (and not known) about the status, values, drivers of change, and responses to management of UK insect pollinators (as was September 2018). This document has been produced to inform the development of England pollinator policy, and provide insight into the evidence that underpins policy decision-making. This document sits alongside a more detailed Summary of Evidence (Annex I) document written by pollinator experts. For information on the development of the statements, and confidence ratings assigned to them, please see section ‘Generation of the statements’ below. Citations for these statements are contained in the Summary of Evidence document

Financing SME growth in the UK: meeting the challenges after the global financial crisis

In the aftermath of the Global Financial Crisis new forms of SME finance are emerging in the place of traditional banking and equity finance sources. This Special Issue has its origins in a conference organised in June 2014 by the Centre for Enterprise and Economic Development Research (CEEDR) at Middlesex University Business School, where all but the final two papers were presented. The Conference was designed to provide a timely forum for leading academics, practitioners and policy makers to disseminate current research and practitioner knowledge exploring finance gaps and how best to address the financing needs of small high growth potential businesses

Eulerian flow velocities in the swash zone: Field data and model predictions

Measurements of Eulerian flow velocity obtained within the swash zone on a relatively steep beach face (gradient 1:23) are compared with an extended ballistic swash model. The model only requires a friction factor, beach slope and terminal bore velocity as input. The following model predictions matched well with observations: (1) The maximum Eulerian flow velocity is the shoreline velocity when it arrives at the fixed point of interest on the beach face; (2) at any location the time of flow reversal occurs prior to the shoreline reaching its maximum landward excursion; (3) the maximum flow velocity in the backwash is the velocity recorded as the shoreline recedes past the fixed point of interest (and this is less than the maximum uprush velocity); and (4) the duration of the uprush flow is shorter than the duration of the backwash flow. Previous studies have already confirmed that the ballistic swash model (including friction) can accurately predict shoreline motion and maximum run-up on steep beaches. This study shows that it is similarly successful in predicting Eulerian flow velocities during individual swash events. The model does not presently account for interacting swash, however, and so may be less appropriate on gently sloping beaches

Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly

The assembly of the tropoelastin monomer into elastin is vital for conferring elasticity on blood vessels, skin, and lungs. Tropoelastin has dual needs for flexibility and structure in self-assembly. We explore the structure-dynamics-function interplay, consider the duality of molecular order and disorder, and identify equally significant functional contributions by local and global structures. To study these organizational stratifications, we perturb a key hinge region by expressing an exon that is universally spliced out in human tropoelastins. We find a herniated nanostructure with a displaced C terminus and explain by molecular modeling that flexible helices are replaced with substantial β sheets. We see atypical higher-order cross-linking and inefficient assembly into discontinuous, thick elastic fibers. We explain this dysfunction by correlating local and global structural effects with changes in the molecule’s assembly dynamics. This work has general implications for our understanding of elastomeric proteins, which balance disordered regions with defined structural modules at multiple scales for functional assembly.United States. Office of Naval Research (Presidential Early Career Award for Scientists and Engineers)National Institutes of Health (U.S.) (U01 EB014976