Retention of Conformational Entropy upon Calmodulin Binding to Target Peptides Is Driven by Transient Salt Bridges

AbstractCalmodulin (CaM) is a highly flexible calcium-binding protein that mediates signal transduction through an ability to differentially bind to highly variable binding sequences in target proteins. To identify how binding affects CaM motions, and its relationship to conformational entropy and target peptide sequence, we have employed fully atomistic, explicit solvent molecular dynamics simulations of unbound CaM and CaM bound to five different target peptides. The calculated CaM conformational binding entropies correlate with experimentally derived conformational entropies with a correlation coefficient R2 of 0.95. Selected side-chain interactions with target peptides restrain interhelical loop motions, acting to tune the conformational entropy of the bound complex via widely distributed CaM motions. In the complex with the most conformational entropy retention (CaM in complex with the neuronal nitric oxide synthase binding sequence), Lys-148 at the C-terminus of CaM forms transient salt bridges alternating between Glu side chains in the N-domain, the central linker, and the binding target. Additional analyses of CaM structures, fluctuations, and CaM-target interactions illuminate the interplay between electrostatic, side chain, and backbone properties in the ability of CaM to recognize and discriminate against targets by tuning its conformational entropy, and suggest a need to consider conformational dynamics in optimizing binding affinities

Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking

Cytoplasmic transport and localization of mRNA has been reported for a range of oocytes and somatic cells. The heterogeneous nuclear ribonucleoprotein (hnRNP) A2 response element (A2RE) is a 21-nucleotide segment of the myelin basic protein mRNA that is necessary and sufficient for cytoplasmic transport of this message in oligodendrocytes, The predominant A2RE-binding protein in rat brain has previously been identified as hnRNP A2, Here we report that an 11-nucleotide subsegment of the A2RE (A2RE11) was as effective as the full-length A2RE in binding hnRNP A2 and mediating transport of heterologous RNA in oligodendrocytes, Point mutations of the A2RE11 that eliminated binding to hnRNP A2 also markedly reduced the ability of these oligoribonucleotides to support RNA transport, Oligodendrocytes treated with antisense oligonucleotides directed against the translation start site of hnRNP A2 had reduced levels of this protein and disrupted transport of microinjected myelin basic protein RNA. Several A2RE-like sequences from localized neuronal RNAs also bound hnRNP A2 and promoted RNA transport in oligo-dendrocytes, These data demonstrate the specificity of A2RE recognition by hnRNP A2, provide direct evidence for the involvement of hnRNP A2 in cytoplasmic RNA transport, and suggest that this protein may interact with a wide variety of localized messages that possess A2RE-like sequences

Response, relaxation and transport in unconventional superconductors

We investigate the collision-limited electronic Raman response and the attenuation of ultrasound in spin-singlet d-wave superconductors at low temperatures. The dominating elastic collisions are treated within a t-matrix approximation, which combines the description of weak (Born) and strong (unitary) impurity scattering. In the long wavelength limit a two-fluid description of both response and transport emerges. Collisions are here seen to exclusively dominate the relaxational dynamics of the (Bogoliubov) quasiparticle system and the analysis allows for a clear connection of response and transport phenomena. When applied to quasi-2-d superconductors like the cuprates, it turns out that the transport parameter associated with the Raman scattering intensity for B1g and B2g photon polarization is closely related to the corresponding components of the shear viscosity tensor, which dominates the attenuation of ultrasound. At low temperatures we present analytic solutions of the transport equations, resulting in a non-power-law behavior of the transport parameters on temperature.Comment: 22 pages, 3 figure

Multiple sequence alignment based on set covers

We introduce a new heuristic for the multiple alignment of a set of sequences. The heuristic is based on a set cover of the residue alphabet of the sequences, and also on the determination of a significant set of blocks comprising subsequences of the sequences to be aligned. These blocks are obtained with the aid of a new data structure, called a suffix-set tree, which is constructed from the input sequences with the guidance of the residue-alphabet set cover and generalizes the well-known suffix tree of the sequence set. We provide performance results on selected BAliBASE amino-acid sequences and compare them with those yielded by some prominent approaches

Electrochemical capacitance of a leaky nano-capacitor

We report a detailed theoretical investigation on electrochemical capacitance of a nanoscale capacitor where there is a DC coupling between the two conductors. For this ``leaky'' quantum capacitor, we have derived general analytic expressions of the linear and second order nonlinear electrochemical capacitance within a first principles quantum theory in the discrete potential approximation. Linear and nonlinear capacitance coefficients are also derived in a self-consistent manner without the latter approximation and the self-consistent analysis is suitable for numerical calculations. At linear order, the full quantum formula improves the semiclassical analysis in the tunneling regime. At nonlinear order which has not been studied before for leaky capacitors, the nonlinear capacitance and nonlinear nonequilibrium charge show interesting behavior. Our theory allows the investigation of crossover of capacitance from a full quantum to classical regimes as the distance between the two conductors is changed

Searches for Stable Strangelets in Ordinary Matter: Overview and a Recent Example

Our knowledge on the possible existence in nature of stable exotic particles depends solely upon experimental observation. Guided by this general principle and motivated by theoretical hypotheses on the existence of stable particles of strange quark matter, a variety of experimental searches have been performed. We provide an introduction to the theoretical hypotheses, an overview of the past searches, and a more detailed description of a recent search for helium-like strangelets in the Earth's atmosphere using a sensitive laser spectroscopy method

A methodology for determining amino-acid substitution matrices from set covers

We introduce a new methodology for the determination of amino-acid substitution matrices for use in the alignment of proteins. The new methodology is based on a pre-existing set cover on the set of residues and on the undirected graph that describes residue exchangeability given the set cover. For fixed functional forms indicating how to obtain edge weights from the set cover and, after that, substitution-matrix elements from weighted distances on the graph, the resulting substitution matrix can be checked for performance against some known set of reference alignments and for given gap costs. Finding the appropriate functional forms and gap costs can then be formulated as an optimization problem that seeks to maximize the performance of the substitution matrix on the reference alignment set. We give computational results on the BAliBASE suite using a genetic algorithm for optimization. Our results indicate that it is possible to obtain substitution matrices whose performance is either comparable to or surpasses that of several others, depending on the particular scenario under consideration

The geomorphological record of an ice stream to ice shelf transition in Northeast Greenland

ACKNOWLEDGEMENTS This work was funded through NERC Standard Grant NE/N011228/1. We thank the Alfred Wegner Institute, and particularly Angelika Humbert and Hicham Rafiq, for their logistic support through the iGRIFF project. Further support was provided from Station Nord (Jorgen Skafte), Nordland Air, Air Greenland, and the Joint Arctic Command. Naalakkersuisut, Government of Greenland, provided Scientific Survey (VU-00121) and Export (046/2017) licences for this work. We thank Chris Orton for help with production of figures. Finally, we would like to thank our Field Ranger Isak (after which Isakdalen is informally named) and dog Ooni for keeping us safe in the field. We thank Rob Storrar and an anonymous reviewer for their comments which helped improve the manuscript.Peer reviewedPublisher PD

A pot of gold at the end of the cosmic "raynbow"?

We critically review the common belief that ultrahigh energy cosmic rays are protons or atomic nuclei with masses not exceeding that of iron. We find that heavier nuclei are indeed possible, and discuss possible sources and acceleration mechanisms for such primaries. We also show detailed simulations of extensive air showers produced by ``superheavy'' nuclei, and discuss prospects for their detection in future experiments.Comment: Talk to be presented at the International Symposium on Very High Energy Cosmic Ray Interactions X

Liquid Crystal Ordering of Four-Base-Long DNA Oligomers with Both G–C and A–T Pairing

We report the liquid crystal (LC) ordering in an aqueous solution of four-base-long DNA oligomers 5\u2032-GCTA-3\u2032. In such systems, the formation of the chiral nematic (N*) LC phase is the result of a continuous self-assembly process in which double helix stability is achieved only through linear chaining of multiple DNA strands. The thermal stability of the aggregates and their LC phase diagram have been experimentally investigated, quantitatively interpreted with theoretical models and compared with recent results on four-base sequences with only G\u2013C or only A\u2013T pairing motifs. N* phase is found at GCTA concentration, cDNA, between 240 and 480 mg/mL and at temperature T < 30 \ub0C. The twist of the nematic director is found to be left-handed with pitch (p) in the optical range, increasing with cDNA and decreasing with T