Disaccharide topology induces slow down in local water dynamics

Molecular level insight into water structure and structural dynamics near proteins, lipids and nucleic acids is critical to the quantitative understanding of many biophysical processes. Un- fortunately, understanding hydration and hydration dynamics around such large molecules is challenging because of the necessity of deconvoluting the effects of topography and chemical heterogeneity. Here we study, via classical all atom simulation, water structure and structural dynamics around two biologically relevant solutes large enough to have significant chemical and topological heterogeneity but small enough to be computationally tractable: the disaccharides Kojibiose and Trehalose. We find both molecules to be strongly amphiphilic (as quantified from normalized local density fluctuations) and to induce nonuniform local slowdown in water translational and rotational motion. Detailed analysis of the rotational slowdown shows that while the rotational mechanism is similar to that previously identified in other aqueous systems by Laage, Hynes and coworkers, two novel characteristics are observed: broadening of the transition state during hydrogen bond exchange (water rotation) and a subpopulation of water for which rotation is slowed because of hindered access of the new accepting water molecule to the transition state. Both of these characteristics are expected to be generic features of water rotation around larger biomolecules and, taken together, emphasize the difficulty in transferring insight into water rotation around small molecules to much larger amphiphilic solutes.This work is part of the research program of the “Stichting voor Fundamenteel Onderzoek der Materie (FOM)” which is financially supported by the “Nederlandse organisatie voor Wetenschap- pelijk Onderzoek (NWO)”. Further financial support was provided by a Marie Curie Incoming International Fellowship (RKC). We gratefully acknowledge SARA, the Dutch center for high- performance computing, for computational time and Huib Bakker and Daan Frenkel for useful critical reviews on an earlier version of this work. We thank two anonymous reviewers for their excellent work, especially for bringing to our attention calculations done on the transition state geometry of dimers and the overstructuring of the O-O radial distribution function of SPC/E water

Computing free energy hypersurfaces for anisotropic intermolecular associations

We previously used an adaptive reaction coordinate force biasing method for calculating the free energy of conformation (Naidoo and Brady, J Am Chem Soc 1999, 121, 2244) and chemical reactions (Rajamani et al., J Comput Chem 2003, 24, 1775) amongst others. Here, we describe a generalized version able to produce free energies in multiple dimensions, descriptively named the free energies from adaptive reaction coordinate forces method. To illustrate it, we describe how we calculate a multidimensional intermolecular orientational free energy, which can be used to investigate complex systems such as protein conformation and liquids. This multidimensional intermolecular free energy W(r, θ1, θ2, ϕ) provides a measure of orientationally dependent interactions that are appropriate for applications in systems that inherently have molecular anisotropic features. It is a highly informative free energy volume, which can be used to parameterize key terms such as the Gay-Berne intermolecular potential in coarse grain simulations. To demonstrate the value of the information gained from the W(r, θ1, θ2, ϕ) hypersurfaces we calculated them for TIP3P, TIP4P, and TIP5P dimer water models in vacuum. A comparison with a commonly used one-dimensional distance free energy profile is made to illustrate the significant increase in configurational information. The W(r) plots show little difference between the three models while the W(r, θ1, θ2, ϕ) hypersurfaces reveal the underlying energetic reasons why these potentials reproduce tetrahedrality in the condensed phase so differently from each

Validating measures of psychological well-being by contrasting samples employed in hazardous and less hazardous work

The study investigated whether differences between contrasting groups reflect significant differences in psychological well-being scores. Membership of hazardous vs. less hazardous occupations in the same profession served as proxy measures of well-being. Antonovsky’s Sense of Coherence (SOC), Block & Kremen’s Ego-resiliency, and Goldberg’s Emotional Stability scales were validated. Study 1 compared mine rescue team members and ordinary miners (n = 34, 41) and Study 2 police special task force members and regular officers (n = 43, 41). In Study 1, SOC and job satisfaction predicted group membership. In Study 2, satisfaction with life and extraversion scales predicted group membership, as did SOC in a secondary analysis. The SOC scale could predict psychological well-being in hazardous work settings

Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase

Item does not contain fulltextTitin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn(31)-Nlinker-kinase-CRD-Ig(26)) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N- and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes

Extreme alien light allows survival of terrestrial bacteria

Photosynthetic organisms provide a crucial coupling between the Sun's energy and metabolic processes supporting life on Earth. Searches for extraterrestrial life focus on seeking planets with similar incident light intensities and environments. However the impact of abnormal photon arrival times has not been considered. Here we present the counterintuitive result that broad classes of extreme alien light could support terrestrial bacterial life whereas sources more similar to our Sun might not. Our detailed microscopic model uses state-of-the-art empirical inputs including Atomic Force Microscopy (AFM) images. It predicts a highly nonlinear survivability for the basic lifeform Rsp. Photometricum whereby toxic photon feeds get converted into a benign metabolic energy supply by an interplay between the membrane's spatial structure and temporal excitation processes. More generally, our work suggests a new handle for manipulating terrestrial photosynthesis using currently-available extreme value statistics photon sources