652 research outputs found
Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes
Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP3-containing membranes. The free energy of interaction of the PH domain with more than two PIP3 molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner
Aerobic Damage to [FeFe]-Hydrogenases: Activation Barriers for the Chemical Attachment of O2.
[FeFe]-hydrogenases are the best natural hydrogen-producing enzymes but their biotechnological exploitation is hampered by their extreme oxygen sensitivity. The free energy profile for the chemical attachment of O2 to the enzyme active site was investigated by using a range-separated density functional re-parametrized to reproduce high-level ab initio data. An activation free-energy barrier of 13 kcal mol(-1) was obtained for chemical bond formation between the di-iron active site and O2 , a value in good agreement with experimental inactivation rates. The oxygen binding can be viewed as an inner-sphere electron-transfer process that is strongly influenced by Coulombic interactions with the proximal cubane cluster and the protein environment. The implications of these results for future mutation studies with the aim of increasing the oxygen tolerance of this enzyme are discussed
A weak characterization of slow variables in stochastic dynamical systems
We present a novel characterization of slow variables for continuous Markov
processes that provably preserve the slow timescales. These slow variables are
known as reaction coordinates in molecular dynamical applications, where they
play a key role in system analysis and coarse graining. The defining
characteristics of these slow variables is that they parametrize a so-called
transition manifold, a low-dimensional manifold in a certain density function
space that emerges with progressive equilibration of the system's fast
variables. The existence of said manifold was previously predicted for certain
classes of metastable and slow-fast systems. However, in the original work, the
existence of the manifold hinges on the pointwise convergence of the system's
transition density functions towards it. We show in this work that a
convergence in average with respect to the system's stationary measure is
sufficient to yield reaction coordinates with the same key qualities. This
allows one to accurately predict the timescale preservation in systems where
the old theory is not applicable or would give overly pessimistic results.
Moreover, the new characterization is still constructive, in that it allows for
the algorithmic identification of a good slow variable. The improved
characterization, the error prediction and the variable construction are
demonstrated by a small metastable system
Evaluating Molecular Mechanical Potentials for Helical Peptides and Proteins
Multiple variants of the AMBER all-atom force field were quantitatively evaluated with respect to their ability to accurately characterize helix-coil equilibria in explicit solvent simulations. Using a global distributed computing network, absolute conformational convergence was achieved for large ensembles of the capped A21 and Fs helical peptides. Further assessment of these AMBER variants was conducted via simulations of a flexible 164-residue five-helix-bundle protein, apolipophorin-III, on the 100 ns timescale. Of the contemporary potentials that had not been assessed previously, the AMBER-99SB force field showed significant helix-destabilizing tendencies, with beta bridge formation occurring in helical peptides, and unfolding of apolipophorin-III occurring on the tens of nanoseconds timescale. The AMBER-03 force field, while showing adequate helical propensities for both peptides and stabilizing apolipophorin-III, (i) predicts an unexpected decrease in helicity with ALA→ARG+ substitution, (ii) lacks experimentally observed 310 helical content, and (iii) deviates strongly from average apolipophorin-III NMR structural properties. As is observed for AMBER-99SB, AMBER-03 significantly overweighs the contribution of extended and polyproline backbone configurations to the conformational equilibrium. In contrast, the AMBER-99φ force field, which was previously shown to best reproduce experimental measurements of the helix-coil transition in model helical peptides, adequately stabilizes apolipophorin-III and yields both an average gyration radius and polar solvent exposed surface area that are in excellent agreement with the NMR ensemble
Mechanical Strength of 17 134 Model Proteins and Cysteine Slipknots
A new theoretical survey of proteins' resistance to constant speed stretching
is performed for a set of 17 134 proteins as described by a structure-based
model. The proteins selected have no gaps in their structure determination and
consist of no more than 250 amino acids. Our previous studies have dealt with
7510 proteins of no more than 150 amino acids. The proteins are ranked
according to the strength of the resistance. Most of the predicted top-strength
proteins have not yet been studied experimentally. Architectures and folds
which are likely to yield large forces are identified. New types of potent
force clamps are discovered. They involve disulphide bridges and, in
particular, cysteine slipknots. An effective energy parameter of the model is
estimated by comparing the theoretical data on characteristic forces to the
corresponding experimental values combined with an extrapolation of the
theoretical data to the experimental pulling speeds. These studies provide
guidance for future experiments on single molecule manipulation and should lead
to selection of proteins for applications. A new class of proteins, involving
cystein slipknots, is identified as one that is expected to lead to the
strongest force clamps known. This class is characterized through molecular
dynamics simulations.Comment: 40 pages, 13 PostScript figure
Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness
<b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p>
<b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p>
<b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts
Analysis of Dentists’ Participation in Continuing Professional Development Courses from 2001-2006
Currently in Western Australia (WA) there is no requirement for dentists to participate in continuing professional development (CPD). The aim of this study was to determine the participation pattern of dentists in WA in CPD activities. Data was collated regarding registrants for courses conducted by the University Continuing Dental Education Committee. Information concerned number of courses attended by each dentist, location of work and year of graduation from university. Details of subject, length and type of courses conducted were also gathered. Most courses were half to one day in duration with many subjects covered. Between 10.1-24.4% of dentists registered in WA attended at least one course each year. Low numbers of recently graduated and older dentists attended courses. Similar percentages of metropolitan and rural dentists attended courses. Participation in CPD activities of dentists in WA was low. Half day or evening courses appear to be favoured by dentists
Extragalactic Radio Continuum Surveys and the Transformation of Radio Astronomy
Next-generation radio surveys are about to transform radio astronomy by
discovering and studying tens of millions of previously unknown radio sources.
These surveys will provide new insights to understand the evolution of
galaxies, measuring the evolution of the cosmic star formation rate, and
rivalling traditional techniques in the measurement of fundamental cosmological
parameters. By observing a new volume of observational parameter space, they
are also likely to discover unexpected new phenomena. This review traces the
evolution of extragalactic radio continuum surveys from the earliest days of
radio astronomy to the present, and identifies the challenges that must be
overcome to achieve this transformational change.Comment: To be published in Nature Astronomy 18 Sept 201
- …