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Contemporary research into community music programmes highlights diverse contexts for collaborative music making. This article contributes a case of the collaboration in music making to a growing literature on creative practice in community music initiatives led by major orchestras. The authors reflect on field research involving an after-school programme that provides free, classical instrumental music instruction to primary school-age students who would not normally have an opportunity due to their socio-economic circumstances. The Pizzicato Effect, run by the Melbourne Symphony Orchestra (MSO) in the City of Hume, Australia has operated in the northern suburbs of Melbourne since 2009. Through focus group interviews with students, family members and teaching artists, the researchers examined community experiences of accruing cultural capital in conditions of social inequality and multicultural practice. Using qualitative methods, the case study aimed to position respondents as experts in their own lives, who own their knowledge of their worlds. Collaboration was central to a model of improvisation developed locally by teaching artists and applied on site. Furthermore, improvisation took the programme in different directions to the El Sistema model of youth orchestra training in Venezuela, which had been the original source of inspiration for the programme. [ABSTRACT FROM AUTHOR]

Classical and contemporary civilizational analysis has not sat comfortably with theoretical constructions of the intercultural or their empirical applications. A 'classical era' of civilizations analysis generated a program of research problems that was productive in critical and multidisciplinary ways and limited in scope and vision in others, but this failed to generate a provisional notion of the intercultural. Contemporary civilizational analysis improves on this position significantly in respect of the intercultural, particularly in the development of a current around 'intercivilizational encounters'. This essay examines this current especially in the work of Benjamin Nelson, Marshall Hodgson and Johann P. Arnason. Arguing that this approach represents vital advances for theoretical constructions of the intercultural in civilizational analysis and more generally in the human sciences, the essay also identifies limitations in latter-day approaches. [ABSTRACT FROM AUTHOR]

Sequence-specific targeting of double-stranded DNA and non-coding RNA via triple-helix-forming peptide nucleic acids (PNAs) has attracted considerable attention in therapeutic, diagnostic and nanotechnological fields. An E-base (3-oxo-2,3-dihydropyridazine), attached to the polyamide backbone of a PNA Hoogsteen strand by a side-chain linker molecule, is typically used in the hydrogen bond recognition of the 4-oxo group of thymine and uracil nucleic acid bases in the major groove. We report on the application of quantum chemical computational methods, in conjunction with spatial constraints derived from the experimental structure of a homopyrimidine PNA·DNA-PNA hetero-triplex, to investigate the influence of linker flexibility on binding interactions of the E-base with thymine and uracil bases in geometry-optimised model systems. Hydrogen bond formation between the N2 E-base atom and target pyrimidine base 4-oxo groups in model systems containing a β-alanine linker (J Am Chem Soc 119:11116, 1997) was found to incur significant internal strain energy and the potential disruption of intra-stand aromatic base stacking interactions in an oligomeric context. In geometry-optimised model systems containing a 3-trans olefin linker (Bioorg Med Chem Lett 14:1551, 2004) the E-base swung out away from the target pyrimidine bases into the solvent. These findings are in qualitative agreement with calorimetric measurements in hybridisation experiments at T–A and U–A inversion sites. In contrast, calculations on a novel 2-cis olefin linker design indicate that it could permit simultaneous E-base hydrogen bonding with the thymine 4-oxo group, circumvention and solvent screening of the thymine 5-methyl group, and maintenance of triplex intra-stand base stacking interactions. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD (HREMD) led to unbiased and accurate ensembles, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of varying sequence properties using two recently optimized force fields, indicating the general applicability of HREMD for IDPs. We further demonstrate that, unlike HREMD, standard MD can reproduce experimental NMR chemical shifts, but not small-angle scattering data, suggesting chemical shifts are insufficient for testing the validity of IDP ensembles. Surprisingly, we reveal that despite differences in their sequence, the inter-chain statistics of all three IDPs are similar for short contour lengths (< 10 residues). The results suggest that the major hurdle of generating an accurate unbiased ensemble for IDPs has now been largely overcome. Shrestha et al. show that enhancing the sampling using Hamiltonian replica exchange molecular simulation (HREMD) leads to accurate unbiased ensembles of intrinsically disordered proteins. They find that standard molecular simulation cannot reproduce small-angle scattering data as well as HREMD, highlighting the utility of the suggested approach. [ABSTRACT FROM AUTHOR]

Lignin solubilization is key to a viable biorefinery because its removal leads to facile deconstruction of biomass and because the isolated lignin can serve to derive precursors of novel high-value materials. The mixing of organic solvents with water has been shown to improve biomass fractionation and lignin conversion reactions. However, generally-applicable solubilization strategies are lacking because of the remarkable variability of lignin across plant feedstocks. Here, to obtain a predictive understanding of lignin solvation, we perform molecular dynamics simulations of model lignin polymers in two mixtures of water with polar aprotic solvents: tetrahydrofuran (THF) : water and γ-valerolactone (GVL) : water. The model lignins include H-, G- and S-only homopolymers and lignins with an S : G 1 : 1 ratio. We find that a well-established theory of self-avoiding polymers in a "good" solvent describes accurately the physical conformations of all types of lignin in both solvents. As the degree of methoxy substitution increases in the homopolymers, the distributions of the lignin radius of gyration and the Flory exponent ν, which describes the lignin-solvent interactions, do not change in THF : water, while ν shifts to slightly higher values in GVL : water. We attribute this increase to the interaction between the methyl group of GVL with the lignin methoxy groups. We also find that the reduction in the lignin radius of gyration due to branching is accurately described by the Zimm–Stockmayer theory for both THF : water and GVL : water. The above findings validate the applicability of polymer physics concepts to lignin and suggest that GVL : water may have the most favorable interaction with S-lignin, whereas the interactions of THF : water with lignin are independent of lignin monomeric content. [ABSTRACT FROM AUTHOR]

Abstract The insertion of nascent polypeptide chains into lipid bilayer membranes and the stability of membrane proteins crucially depend on the equilibrium partitioning of polypeptides. For this, the transfer of full sequences of amino-acid residues into the bilayer, rather than individual amino acids, must be understood. Earlier studies have revealed that the most likely reference state for partitioning very hydrophobic sequences is the membrane interface. We have used μs-scale simulations to calculate the interface-to-transmembrane partitioning free energies ΔG S→TM for two hydrophobic carrier sequences in order to estimate the insertion free energy for all 20 amino acid residues when bonded to the center of a partitioning hydrophobic peptide. Our results show that prior single-residue scales likely overestimate the partitioning free energies of polypeptides. The correlation of ΔG S→TM with experimental full-peptide translocon insertion data is high, suggesting an important role for the membrane interface in translocon-based insertion. The choice of carrier sequence greatly modulates the contribution of each single-residue mutation to the overall partitioning free energy. Our results demonstrate the importance of quantifying the observed full-peptide partitioning equilibrium, which is between membrane interface and transmembrane inserted, rather than combining individual water-to-membrane amino acid transfer free energies. Graphical abstract Unlabelled Image Highlights • The insertion of polypeptide chains into lipid bilayer membranes depends on the interface-to-transmembrane free energies for full peptides • Long-scale fully atomistic simulations now allow direct computation of fullpeptide insertion free energies • Correlation with full-peptide translocon insertion data suggests an important role for the membrane interface in translocon-based insertion. • The relevant reference state for membrane insertion is the surface state, rather than a water soluble state [ABSTRACT FROM AUTHOR]

Dynamic neutron scattering directly probes motions in biological systems on femtosecond to microsecond timescales. When combined with molecular dynamics simulation and normal mode analysis, detailed descriptions of the forms and frequencies of motions can be derived. We examine vibrations in proteins, the temperature dependence of protein motions, and concepts describing the rich variety of motions detectable using neutrons in biological systems at physiological temperatures. New techniques for deriving information on collective motions using coherent scattering are also reviewed. [ABSTRACT FROM AUTHOR]

Channel and pump rhodopsins use energy from light absorbed by a covalently bound retinal chromophore to transport ions across membranes of microbial cells. Ion transfer steps, including proton transfer, can couple to changes in protein conformational dynamics and water positions. Although general principles of how microbial rhodopsins function are largely understood, key issues pertaining to reaction mechanisms remain unclear. In this review, we compare the protonation-coupled dynamics of pump and channelrhodopsins, highlighting the roles that water dynamics, protein electrostatics and protein flexibility can have in ion transport mechanisms. We discuss observations supporting important functional roles of inter- and intra-helical carboxylate/hydroxyl hydrogen-bonding motifs. As specific examples, we use the proton pump bacteriorhodopsin, the sodium pump KR2, channelrhodopsins and Anabaena sensory rhodopsin. We outline the usefulness of theoretic biophysics approaches to the study of retinal proteins, challenges in studying the hydrogen-bond dynamics of rhodopsin active sites, and implications for conformational coupling in membrane transporters. [ABSTRACT FROM AUTHOR]

Understanding of cell membrane organization has evolved significantly from the classic fluid mosaic model. It is now recognized that biological membranes are highly organized structures, with differences in lipid compositions between inner and outer leaflets and in lateral structures within the bilayer plane, known as lipid rafts. These organizing principles are important for protein localization and function as well as cellular signaling. However, the mechanisms and biophysical basis of lipid raft formation, structure, dynamics and function are not clearly understood. One key question, which we focus on in this review, is how lateral organization and leaflet compositional asymmetry are coupled. Detailed information elucidating this question has been sparse because of the small size and transient nature of rafts and the experimental challenges in constructing asymmetric bilayers. Resolving this mystery will require advances in both experimentation and modeling. We discuss here the preparation of model systems along with experimental and computational approaches that have been applied in efforts to address this key question in membrane biology. We seek to place recent and future advances in experimental and computational techniques in context, providing insight into in-plane and transverse organization of biological membranes. [ABSTRACT FROM AUTHOR]

Relative amino acid residue solvent accessibility values allow the quantitative comparison of atomic solvent-accessible surface areas in different residue types and physical environments in proteins and in protein structural alignments. Geometry-optimised tri-peptide structures in extended solvent-exposed reference conformations have been obtained for 43 amino acid residue types at a high level of quantum chemical theory. Significant increases in side-chain solvent accessibility, offset by reductions in main-chain atom solvent exposure, were observed for standard residue types in partially geometry-optimised structures when compared to non-minimised models built from identical sets of proper dihedral angles abstracted from the literature. Optimisation of proper dihedral angles led most notably to marked increases of up to 54% in proline main-chain atom solvent accessibility compared to literature values. Similar effects were observed for fully-optimised tri-peptides in implicit solvent. The relief of internal strain energy was associated with systematic variation in N, C α and C β atom solvent accessibility across all standard residue types. The results underline the importance of optimisation of ‘hard’ degrees of freedom (bond lengths and valence bond angles) and improper dihedral angle values from force field or other context-independent reference values, and impact on the use of standardised fixed internal co-ordinate geometry in sampling approaches to the determination of absolute values of protein amino acid residue solvent accessibility. Quantum chemical methods provide a useful and accurate alternative to molecular mechanics methods to perform energy minimisation of peptides containing non-standard (chemically modified) amino acid residues frequently present in experimental protein structure data sets, for which force field parameters may not be available. Reference tri-peptide atomic co-ordinate sets including hydrogen atoms are made freely available. [ABSTRACT FROM AUTHOR]

Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor (FGFR), α-Klotho, and heparin sulfate. These structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling. [ABSTRACT FROM AUTHOR]

Background: In a previous paper, we classified populated HLA class I alleles into supertypes and subtypes based on the similarity of 3D landscape of peptide binding grooves, using newly defined structure distance metric and hierarchical clustering approach. Compared to other approaches, our method achieves higher correlation with peptide binding specificity, intra-cluster similarity (cohesion), and robustness. Here we introduce HLA-Clus, a Python package for clustering HLA Class I alleles using the method we developed recently and describe additional features including a new nearest neighbor clustering method that facilitates clustering based on user-defined criteria. Results: The HLA-Clus pipeline includes three stages: First, HLA Class I structural models are coarse grained and transformed into clouds of labeled points. Second, similarities between alleles are determined using a newly defined structure distance metric that accounts for spatial and physicochemical similarities. Finally, alleles are clustered via hierarchical or nearest-neighbor approaches. We also interfaced HLA-Clus with the peptide:HLA affinity predictor MHCnuggets. By using the nearest neighbor clustering method to select optimal allele-specific deep learning models in MHCnuggets, the average accuracy of peptide binding prediction of rare alleles was improved. Conclusions: The HLA-Clus package offers a solution for characterizing the peptide binding specificities of a large number of HLA alleles. This method can be applied in HLA functional studies, such as the development of peptide affinity predictors, disease association studies, and HLA matching for grafting. HLA-Clus is freely available at our GitHub repository (https://github.com/yshen25/HLA-Clus). [ABSTRACT FROM AUTHOR]

Polypharmacology, the ability of drugs to interact with multiple targets, is a fundamental concept of interest to the pharmaceutical industry in its efforts to solve the current issues of the rise in the cost of drug development and decline in productivity. Polypharmacology has the potential to greatly benefit drug repurposing, bringing existing pharmaceuticals on the market to treat different ailments quicker and more affordably than developing new drugs, and may also facilitate the development of new, potent pharmaceuticals with reduced negative off-target effects and adverse side effects. Present day computational power, when combined with applications such as supercomputer-based virtual high-throughput screening (docking) will enable these advances on a massive chemogenomic level, potentially transforming the pharmaceutical industry. However, while the potential of supercomputing-based drug discovery is unequivocal, the technical and fundamental challenges are considerable. [ABSTRACT FROM AUTHOR]

Proteins display characteristic dynamical signatures that appear to be universal across all proteins regardless of topology and size. Here, we systematically characterize the universal features of fast side chain motions in proteins by examining the conformational energy surfaces of individual residues obtained using enhanced sampling molecular dynamics simulation (618 free energy surfaces obtained from 0.94 μs MD simulation). The side chain conformational free energy surfaces obtained using the adaptive biasing force (ABF) method for a set of eight proteins with different molecular weights and secondary structures are used to determine the methyl axial NMR order parameters (Oaxis2), populations of side chain rotamer states (ρ), conformational entropies (Sconf), probability fluxes, and activation energies for side chain interrotameric transitions. The free energy barriers separating side chain rotamer states range from 0.3 to 12 kcal/mol in all proteins and follow a trimodal distribution with an intense peak at ∼5 kcal/mol and two shoulders at ∼3 and ∼7.5 kcal/mol, indicating that some barriers are more favored than others by proteins to maintain a balance between their conformational stability and flexibility. The origin and the influences of the trimodal barrier distribution on the distribution of Olxis and the side chain conformational entropy are discussed. A hierarchical grading of rotamer states based on the conformational free energy barriers, entropy, and probability flux reveals three distinct classes of side chains in proteins. A unique nonlinear correlation is established between Oaxis2 and the side chain rotamer populations (ρ). The apparent universality in Oaxis2 versus ρ correlation, trimodal barrier distribution, and distinct characteristics of three classes of side chains observed among all proteins indicates a hidden regularity (or commonality) in the dynamical heterogeneity of fast side chain motions in proteins. [ABSTRACT FROM AUTHOR]

Starting from Peter Wagner's insight about the re-theorization of modernity, this article sketches a theoretical framework to incorporate the interpretations of modernity which go beyond the domination of a single Western or European perspective. Much theorization of modernity has been European-centered to the neglect of rich social and cultural thought from other regions of the world. The rise of indigenous activism in Latin America has provided the world with an example of different kinds of activism, and distinct forms of cultural and political thought and practice. This article takes the bold step in arguing that Latin America's indigenous movements have generated a fresh and alternative interpretation of modernity. Those movements which have emerged over the course of the last three decades have pursued a different vision of recognition, sovereignty and ecology and bring to that pursuit a new kind of social and political agency. Unlike conventional philosophies of statehood derived from the Westphalian tradition of state-making, indigenous perspectives privilege new kinds of coexistence. Moreover, the different ontological relationship with Nature that they posit also has potentially significant implications for addressing climate change. [ABSTRACT FROM AUTHOR]

The 2013 Nobel Prize in Chemistry has been awarded to Martin Karplus, Michael Levitt, and Arieh Warshel for their work on developing computational methods to study complex chemical systems. Their work has led to mechanistic critical insights into chemical systems both large and small and has enabled progress in a number of different fields, including structural biology. [ABSTRACT FROM AUTHOR]

The program VinaMPI has been developed to enable massively large virtual drug screens on leadership-class computing resources, using a large number of cores to decrease the time-to-completion of the screen. VinaMPI is a massively parallel Message Passing Interface (MPI) program based on the multithreaded virtual docking program AutodockVina, and is used to distribute tasks while multithreading is used to speed-up individual docking tasks. VinaMPI uses a distribution scheme in which tasks are evenly distributed to the workers based on the complexity of each task, as defined by the number of rotatable bonds in each chemical compound investigated. VinaMPI efficiently handles multiple proteins in a ligand screen, allowing for high-throughput inverse docking that presents new opportunities for improving the efficiency of the drug discovery pipeline. VinaMPI successfully ran on 84,672 cores with a continual decrease in job completion time with increasing core count. The ratio of the number of tasks in a screening to the number of workers should be at least around 100 in order to have a good load balance and an optimal job completion time. The code is freely available and downloadable. Instructions for downloading and using the code are provided in the Supporting Information. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The interaction between two associating hydrophobic particles has traditionally been explained in terms of the release of entropically frustrated hydration shell water molecules. However, this picture cannot account for the kinetics of hydrophobic association and is therefore not capable of providing a microscopic description of the hydrophobic interaction (HI). Here, Monte Carlo simulations of a pair of molecular-scale apolar solutes in aqueous solution reveal the critical role of collective fluctuations in the hydrogen bond (HB) network for the microscopic picture of the HI. The main contribution to the HI is the relaxation of solute-water translational correlations. The existence of a heat capacity maximum at the desolvation barrier is shown to arise from softening of non-HB water fluctuations and the relaxation of many-body correlations in the labile HB network. The microscopic event governing the kinetics of hydrophobic association has turned out to be a relatively large critical collective fluctuation in hydration water displacing a substantial fraction of HB clusters from the inner to the outer region of the first hydration shell. [ABSTRACT FROM AUTHOR]

An analytical approach is developed for reconstructingsite-specificmethyl-bearing protein side-chain conformational energy surfaces fromNMR methyl axis order parameters (Oaxis2). Application of an enhancedsampling algorithm (adaptive biasing force) to molecular dynamicssimulation of a protein, calcium-bound calmodulin, reveals a nonlinearcorrelation between Oaxis2and the populations of rotamer statesof protein side-chains, permitting the rotamer populations to be extracteddirectly from Oaxis2. The analytical approach yields side-chainconformational distributions that are in excellent agreement withthose obtained from the enhanced-sampling MD results. [ABSTRACT FROM AUTHOR]

An essay on the political imaginary and its relevance on the American political formation. It explores the articulations of political philosophers Cornelius Castoriadis and Claude Lefort of concepts on human autonomy, political power, and democracy, presenting contrasts in their view of the U.S. Constitution. It also examines aspects of the political imaginary in the works of Thomas Jefferson and Simon Bolivar.

An introduction to the journal is presented in which the editors discuss various articles published within the issue including expositions on the works of political philosophers Cornelius Castoriadis and Claude Lefort on the concepts of the social imaginaries, social doing, and democracy.

Monte Carlo simulations of a small model solute in an aqueous solution are used to examine the effects of solute polarity on hydration structure. A judicious definition of the orientational order parameter leads to reinterpretation of the conventional picture of hydration. As the solute varies from hydrophobic to hydrophilic the ordered first shell water simultaneously fractionates into a more highly ordered and a more disordered component. The hydrogen-bond network rearranges such that the more ordered component relaxes to configurations of optimal intermolecular angles, the other fraction being released from the network. [ABSTRACT FROM AUTHOR]

Nascent transmembrane (TM) polypeptide segments are recognized and inserted into the lipid bilayer by the cellular translocon machinery. The recognition rules, described by a biological hydrophobicity scale, correlate strongly with physical hydrophobicity scales that describe the free energy of insertion of TM helices from water. However, the exact relationship between the physical and biological scales is unknown, because solubility problems limit our ability to measure experimentally the direct partitioning of hydrophobic peptides across lipid membranes. Here we use microsecond molecular dynamics (MD) simulations in which monomeric polyleucine segments of different lengths are allowed to partition spontaneously into and out of lipid bilayers. This approach directly reveals all states populated at equilibrium. For the hydrophobic peptides studied here, only surface-bound and transmembrane-inserted helices are found. The free energy of insertion is directly obtained from the relative occupancy of these states. A water-soluble state was not observed, consistent with the general insolubility of hydrophobic peptides. The approach further allows determination of the partitioning pathways and kinetics. Surprisingly, the transfer free energy appears to be independent of temperature, which implies that surface-to-bilayer peptide insertion is a zero-entropy process. We find that the partitioning free energy of the polyleucine segments correlates strongly with values from translocon experiments but reveals a systematic shift favoring shorter peptides, suggesting that translocon-to-bilayer partitioning is not equivalent but related to spontaneous surface-to-bilayer partitioning. [ABSTRACT FROM AUTHOR]

Johann Arnason’s exploration of the historical constellation of East Asia has helped reproblematize the conceptual framework of modernity and civilization. This article outlines Arnason’s innovations in civilizational analysis and social theory in the field of comparative studies of Japan. It sets out the terms on which a nuanced elaboration of Arnason’s framework could occur. Two areas warrant closer attention: state formation and the institution of capitalism. It is argued that there are signs of what might be termed a ‘tertiary’ phase of state formation, implicit in Arnason’s discussion of advanced modernity. Moreover, this phase brought Japan into close contact with the newly unfolding context of the West’s civilizational imaginary, particularly in its ideological expressions of evolutionism. The article ends on the problematic of capitalism, raising questions about further potential theoretical developments based on Arnason’s conclusions and other inventive studies of Japanese capitalism. [ABSTRACT FROM PUBLISHER]

The recalcitrance of lignocellulosic biomass to hydrolysis is the bottleneck in cellulosic ethanol production. Efficient degradation of biomass by the anaerobic bacterium Clostridium thermocellum is carried out by the multicomponent cellulosome complex. The bacterial cell-surface attachment of the cellulosome is mediated by high-affinity protein–protein interactions between the Type II cohesin domain borne by the cell envelope protein and the Type II dockerin domain, together with neighboring X-module present at the C-terminus of the scaffolding protein (Type II coh–Xdoc). Here, the Type II coh–Xdoc interaction is probed using molecular dynamics simulations, free-energy calculations and essential dynamics analyses on both the wild type and various mutants of the C. thermocellum Type II coh–Xdoc in aqueous solution. The simulations identify the hot spots, i.e. the amino acid residues that may lead to a dramatic decrease in binding affinity upon mutation and also probe the effects of mutations on the mode of binding. The results suggest that bulky and hydrophobic residues at the protein interface, which make specific contacts with their counterparts, may play essential roles in retaining a rigid cohesin–dockerin interface. Moreover, dynamical cross-correlation analysis indicates that the X-module has a dramatic effect on the cohesin–dockerin interaction and is required for the dynamical integrity of the interface. [ABSTRACT FROM PUBLISHER]

Understanding the mechanism of proton pumping requires a detailed description of the energetics and sequence of events associated with the proton transfers, and of how proton transfer couples to conformational rearrangements of the protein. Here, we discuss our recent advances in using computer simulations to understand how bacteriorhodopsin pumps protons. We emphasize the importance of accurately describing the retinal geometry and the location of water molecules. [ABSTRACT FROM AUTHOR]

The folding of a 15-residue β-hairpin peptide (Peptide 1) is characterized using multiple unbiased, atomistic molecular dynamics (MD) simulations. Fifteen independent MD trajectories, each 2.5 μs-long for a total of 37.5 μs, are performed of the peptide in explicit solvent, at room temperature, and without the use of enhanced sampling techniques. The computed folding time of 1-1.5 eμs obtained from the simulations is in good agreement with experiment [Xu, Y.; et al. J. Am. Chem. Soc. 2003, 125, 15388-15394]. A common folding mechanism is observed, in which the turn is always found to be the major determinant in initiating the folding process, followed by cooperative formation of the interstrand hydrogen bonds and the side-chain packing. Furthermore, direct transition to the folded state from fully unstructured conformations does not take place. Instead, the peptide is always observed to form partially structured conformations involving a non-native (ESYI) turn from which the native (NPDG) turn forms, triggering the folding to the β-hairpin. [ABSTRACT FROM AUTHOR]

Changes in the free energy barrier (ΔF), entropy, and motional parameters associated with the rotation of methyl groups in a protein (calmodulin (CaM)) on binding a ligand (the calmodulin-binding domain of smooth-muscle myosin (smMLCKp)) are investigated using molecular dynamics simulation. In both the bound and uncomplexed forms of CaM, the methyl rotational free energy barriers follow skewed-Gaussian distributions that are not altered significantly upon ligand binding. However, site-specific perturbations are found. Around 11% of the methyl groups in CaM exhibit changes in ΔE greater than 0.7 kcal/mol on binding. The rotational entropies of the methyl groups exhibit a nonlinear dependence on ΔE. The relations are examined between motional parameters (the methyl rotational NMR order parameter and the relaxation time) and ΔE. Low-barrier methyl group rotational order parameters deviate from ideal tetrahedrality by up to ∼20%. There is a correlation between rotational barrier changes and proximity to the protein-peptide binding interface. Methyl groups that exhibit large changes in ΔE are found to report on elements in the protein undergoing structural change on binding. [ABSTRACT FROM AUTHOR]

The proton pumping cycle of bacteriorhodopsin consists of five consecutive proton transfer steps, in all of which water molecules are likely to play critical roles. Here we review the role of water molecules in bacteriorhodopsin function, with emphasis on computations of the retinal Schiff base deprotonation reaction and the open questions regarding the participation of water molecules in the longer-distance proton transfer reactions. [ABSTRACT FROM AUTHOR]

A CHARMM molecular mechanics force field for lignin is derived. Parameterization is based on reproducing quantum mechanical data of model compounds. Partial atomic charges are derived using the RESP electrostatic potential fitting method supplemented by the examination of methoxybenzene:water interactions. Dihedral parameters are optimized by fitting to critical rotational potentials and bonded parameters are obtained by optimizing vibrational frequencies and normal modes. Finally, the force field is validated by performing a molecular dynamics simulation of a crystal of a lignin fragment molecule and comparing simulation-derived structural features with experimental results. Together with the existing force field for polysaccharides, this lignin force field will enable full simulations of lignocellulose. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

Abstract: The positional preferences of the twenty amino-acid residues in a phospholipid bilayer are investigated by calculating the solvation free energy of the corresponding side chain analogues using a five-slab continuum electrostatic model. The side-chain analogues of the aromatic residues tryptophan and tyrosine are found to partition in the head-group region, due to compensation between the increase of the non-polar component of the solvation free energy at the boundary with the aqueous region and the decrease in the electrostatic component. The side chain analogue of phenylalanine differs from the other aromatic molecules by being able to partition in both the head-group region and the membrane core. This finding is consistent with experimental findings of the position of phenylalanine in membrane helices. Interestingly, the charged side-chain analogues of arginine and lysine are shown to prefer the head-group region in an orientation that allows the charged moiety to interact with the aqueous layer. The orientation adopted is similar to the “snorkelling” effect seen in lysine and arginine residues in membrane helices. In contrast, the preference of the charged side-chain analogues of histidine (protonated) and aspartate (deprotonated) for the aqueous layer is shown to be due to a steep decrease in the electrostatic component of the solvation free energy at the boundary to the aqueous region. The calculations allow an understanding of the origins of side chain positioning in membranes and are thus useful in understanding membrane–protein:lipid thermodynamics. [Copyright &y& Elsevier]

Atomistic molecular dynamics simulations are used to investigate the mechanism by which the antifreeze protein from the spruce budworm, Choristoneura fumiferana, binds to ice. Comparison of structural and dynamic properties of the water around the three faces of the triangular prism-shaped protein in aqueous solution reveals that at low temperature the water structure is ordered and the dynamics slowed down around the ice-binding face of the protein, with a disordering effect observed around the other two faces. These results suggest a dual role for the solvation water around the protein. The preconfigured solvation shell around the ice-binding face is involved in the initial recognition and binding of the antifreeze protein to ice by lowering the barrier for binding and consolidation of the protein:ice interaction surface. Thus, the antifreeze protein can bind to the molecularly rough ice surface by becoming actively involved in the formation of its own binding site. Also, the disruption of water structure around the rest of the protein helps prevent the adsorbed protein becoming covered by further ice growth. [ABSTRACT FROM AUTHOR]

Microscopic statistical pressure fluctuations can, in principle, lead to corresponding fluctuations in the shape of a protein energy landscape. To examine this, nanosecond molecular dynamics simulations of lysozyme are performed covering a range of temperatures and pressures. The well known dynamical transition with temperature is found to be pressure-independent, indicating that the effective energy barriers separating conformational substates are not significantly influenced by pressure. In contrast, vibrations within substates stiffen with pressure, due to increased curvature of the local harmonic potential in which the atoms vibrate. The application of pressure is also shown to selectively increase the damping of the anharmonic, low-frequency collective modes in the protein, leaving the more local modes relatively unaffected. The critical damping frequency, i.e., the frequency at which energy is most efficiently dissipated, increases linearly with pressure. The results suggest that an invariant description of protein energy landscapes should be subsumed by a fluctuating picture and that this may have repercussions in, for example, mechanisms of energy dissipation accompanying functional, structural, and chemical relaxation. [ABSTRACT FROM AUTHOR]

Summary: Before the myosin motor head can perform the next power stroke, it undergoes a large conformational transition in which the converter domain, bearing the lever arm, rotates ∼65°. Simultaneous with this “recovery stroke,” myosin activates its ATPase function by closing the Switch-2 loop over the bound ATP. This coupling between the motions of the converter domain and of the 40 Å-distant Switch-2 loop is essential to avoid unproductive ATP hydrolysis. The coupling mechanism is determined here by finding a series of optimized intermediates between crystallographic end structures of the recovery stroke (Dictyostelium discoideum), yielding movies of the transition at atomic detail. The successive formation of two hydrogen bonds by the Switch-2 loop is correlated with the successive see-saw motions of the relay and SH1 helices that hold the converter domain. SH1 helix and Switch-2 loop communicate via a highly conserved loop that wedges against the SH1-helix upon Switch-2 closing. [Copyright &y& Elsevier]

Abstract: During the recovery stroke, the myosin motor is primed for the next power stroke by a 60° rotation of its lever arm. This reversible motion is coupled to the activation of the ATPase function of myosin through conformational changes along the relay helix, which runs from the Switch-2 loop near the ATP to the converter domain carrying the lever arm. Via a hydrogen bond between the side-chain of Asn475 on the relay helix and the Gly457/Ser456 peptide group on the Switch-2, the rotation of the converter domain is coupled to the formation of a hydrogen bond between Gly457 and γ-phosphate that is essential for ATP hydrolysis. Here, molecular dynamics simulations of Dictyostelium discoideum myosin II in the two end conformations of the recovery stroke with different nucleotide states (ATP, ADP·Pi, ADP) reveal that the side-chain of Asn475 breaks away from Switch-2 upon ATP hydrolysis to make a hydrogen bond with Tyr573. This sensing of the nucleotide state is achieved by a small displacement of the cleaved γ-phosphate towards Gly457 which in turn pushes Asn475 away. The sensing plays a dual role by (i) preventing the wasteful reversal of the recovery stroke while the nucleotide is in the ADP·Pi state, and (ii) decoupling the relay helix from Switch-2, thus allowing the power stroke to start upon initial binding to actin while Gly457 of Switch-2 keeps interacting with the Pi (known to be released only later after tight actin binding). A catalytically important salt bridge between Arg238 (on Switch-1) and Glu459 (on Switch-2), which covers the hydrolysis site, is seen to form rapidly when ATP is added to the pre-recovery stroke conformer and remains stable after the recovery stroke, indicating that it has a role in shaping the ATP binding site by induced fit. [Copyright &y& Elsevier]

The molecular motor myosin converts chemical energy from ATP hydrolysis into mechanical work, thus driving a variety of essential motility processes. Although myosin function has been studied extensively, the catalytic mechanism of ATP hydrolysis and its chemomechanical coupling to the motor cycle are not completely understood. Here, the catalysis mechanism in myosin II is examined using quantum mechanical/molecular mechanical reaction path calculations. The resulting reaction pathways, found in the catalytically competent closed/closed conformation of the Switch-1/Switch-2 loops of myosin, are all associative with a pentavalent bipyramidal oxyphosphorane transition state but can vary in the activation mechanism of the attacking water molecule and in the way the hydrogens are transferred between the heavy atoms. The coordination bond between the Mg2+ metal cofactor and Ser237 in the Switch-1 loop is broken in the product state, thereby facilitating the opening of the Switch-1 loop after hydrolysis is completed, which is required for subsequent strong rebinding to actin. This reveals a key element of the chemomechanical coupling that underlies the motor cycle, namely, the modulation of actin unbinding or binding in response to the ATP or ADP-Pi state of nucleotide-bound myosin. [ABSTRACT FROM AUTHOR]

An understanding of low-frequency, collective protein dynamics at low temperatures can furnish valuable information on functional protein energy landscapes, on the origins of the protein glass transition and on protein-protein interactions. Here, molecular dynamics (MD) simulations and normal-mode analyses are performed on various models of crystalline myoglobin in order to characterize intra- and interprotein vibrations at 150 K. Principal component analysis of the MD trajectories indicates that the Boson peak, a broad peak in the dynamic structure factor centered at about ∼2-2.5 meV, originates from ∼10² collective, harmonic vibrations. An accurate description of the environment is found to be essential in reproducing the experimental Boson peak form and position. At lower energies other strong peaks are found in the calculated dynamic structure factor. Characterization of these peaks shows that they arise from harmonic vibrations of proteins relative to each other. These vibrations are likely to furnish valuable information on the physical nature of protein-protein interactions. [ABSTRACT FROM AUTHOR]

A parameterization has been performed of the biologically important sterols cholesterol, ergosterol, and lanosterol for the CHARMM27 all-atom molecular mechanics force field. An automated parameterization method was used that involves fitting the potential to vibrational frequencies and eigenvectors derived from quantum-chemical calculations. The partial charges were derived by fitting point charges to quantum-chemically calculated electrostatic potentials. To model the dynamics of the hydroxyl groups of the sterols correctly, the parameter set was refined to reproduce the energy barrier for the rotation of the hydroxyl group around the carbon connected to the hydroxyl of each sterol. The frequency-matching plots show good agreement between the CHARMM and quantum chemical normal modes. The parameters are tested in a molecular dynamics simulation of the cholesterol crystal structure. The experimental geometry and cell dimensions are well reproduced. The force field derived here is also useful for simulating other sterols such as the phytosterols sigmasterol, and campesterol, and a variety of steroids. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1383–1399, 2005 [ABSTRACT FROM AUTHOR]

The modification of internal vibrational modes in a protein due to intraprotein anharmonicity and solvation effects is determined by performing molecular dynamics (MD) simulations of myoglobin, analyzing them using a Langevin model of the vibrational dynamics and comparing the Langevin results to a harmonic, normal mode model of the protein in vacuum. The diagonal and off-diagonal Langevin friction matrix elements, which model the roughness of the vibrational potential energy surfaces, are determined together with the vibrational potentials of mean force from the MD trajectories at 120 K and 300 K in vacuum and in solution. The frictional properties are found to be describable using simple phenomenological functions of the mode frequency, the accessible surface area, and the intraprotein interaction (the displacement vector overlap of any given mode with the other modes in the protein). The frictional damping of a vibrational mode in vacuum is found to be directly proportional to the intraprotein interaction of the mode, whereas in solution, the friction is proportional to the accessible surface area of the mode. In vacuum, the MD frequencies are lower than those of the normal modes, indicating intramolecular anharmonic broadening of the associated potential energy surfaces. Solvation has the opposite effect, increasing the large-amplitude vibrational frequencies relative to in vacuum and thus vibrationally confining the protein atoms. Frictional damping of the low-frequency modes is highly frequency dependent. In contrast to the damping effect of the solvent, the vibrational frequency increase due to solvation is relatively temperature independent, indicating that it is primarily a structural effect. The MD-derived vibrational dynamic structure factor and density of states are well reproduced by a model in which the Langevin friction and potential of mean force parameters are applied to the harmonic normal modes. [ABSTRACT FROM AUTHOR]

A novel power supply protection clamp is presented which incorporates feedback techniques to improve ESD and normal operational mode behavior. The design uses a short duration RC trigger, which enables the clamp to tolerate very fast power supply ramp rates and exhibit reduced area and leakage. The design is built in a 90 nm CMOS technology with fully salicided source/drain regions. [Copyright &y& Elsevier]

Johann Arnason and Shmuel Eisenstadt's social theories have remarkably different origins. Yet each has moved onto common ground with the other over a period of time. They meet in historical sociology in dialogue over theories of state formation and images of civilisation. Each is engaged in a project of revising civilisations sociology that reaches an apex with the comparative study of Japan.Their groundbreaking contributions can be read critically against a wider background of debates about postcolonialism, the reputation of the notion of civilisation and the state of area studies in the humanities and social sciences. [ABSTRACT FROM AUTHOR]

Examines the hydration shell of lysozyme for high density of bulk water. Characterization on the physical properties of protein surface hydration water; Use of molecular simulation to indicate the density of water; Determination on the topographical and electrostatic properties on protein surfaces.

Pretreatment facilitates cost-effective operations on lignocellulosic biomass ranging from densification to deconstruction and bioproduct development. However, determining molecular-level mechanisms behind pretreatment and their effects has remained elusive. Here, we combine computational simulation and experiment to investigate the effects on wheat straw agricultural residue densification of an emerging pretreatment solvent, namely, a deep eutectic solvent (DES) consisting of choline chloride (ChCl) and oxalic acid (OA). Ab initio molecular dynamics indicates that dissociation of lignin from cellulose in lignin–carbohydrate complexes, which does not occur to a significant extent in aqueous solution, is favorable in the DES and occurs via cleavage of the guaiacyl : xylose ether bond linkage by OA. The ensuing hemicellulose removal exposes lignin to the DES which, molecular dynamics simulation indicates, leads to lignin expansion. The resulting changes in wheat straw fiber structure, lignin distribution, and functional group modifications upon DES treatment by scanning electron and fluorescence microscopy along with Fourier-transform infrared spectroscopy. The molecular expansion of lignin enhances inter-particle binding in wheat straw, leading to denser structures under pelletization. The resulting high mechanical stability and combustion properties make the wheat straw a suitable precursor of high-quality densified solids (e.g., solid biofuel). Overall, we shed light on the molecular-level mechanisms involved in DES pretreatment for biomass densification, demonstrated here in the development of a solid biofuel. The approach here illuminates the rational design from first chemical principles of methods to convert lignocellulosic resources into advanced materials. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators. [ABSTRACT FROM AUTHOR]

Knowledge of the physical properties of ionic liquids (ILs), such as the surface tension and speed of sound, is important for both industrial and research applications. Unfortunately, technical challenges and costs limit exhaustive experimental screening efforts of ILs for these critical properties. Previous work has demonstrated that the use of quantum-mechanics-based thermochemical property prediction tools, such as the conductor-like screening model for real solvents, when combined with machine learning (ML) approaches, may provide an alternative pathway to guide the rapid screening and design of ILs for desired physiochemical properties. However, the question of which machine-learning approaches are most appropriate remains. In the present study, we examine how different ML architectures, ranging from tree-based approaches to feed-forward artificial neural networks, perform in generating nonlinear multivariate quantitative structure–property relationship models for the prediction of the temperature- and pressure-dependent surface tension of and speed of sound in ILs over a wide range of surface tensions (16.9–76.2 mN/m) and speeds of sound (1009.7–1992 m/s). The ML models are further interrogated using the powerful interpretation method, shapley additive explanations. We find that several different ML models provide high accuracy, according to traditional statistical metrics. The decision tree-based approaches appear to be the most accurate and precise, with extreme gradient-boosting trees and gradient-boosting trees being the best performers. However, our results also indicate that the promise of using machine-learning to gain deep insights into the underlying physics driving structure–property relationships in ILs may still be somewhat premature. [ABSTRACT FROM AUTHOR]

Far-infrared absorption spectroscopy gives information on the charge fluctuations associated with hydrogen-bond dynamics in water. Here, we examine these fluctuations by calculating spectra from molecular dynamics simulations and comparing with experiment. Permanent and induced dipoles are included in the calculation of the system dipole moment. The induced dipoles are calculated on each atom using an iterative method that leads to self-consistency of the induced dipole contribution to the local field. The experimental far-infrared spectrum has two prominent bands, at ~ 600 cm-1 and ~ 200 cm-1 , due to hydrogen-bond libration and stretching, respectively. The librational band is found to arise from fluctuations of the positions of the permanent charges in the simulation, whereas the stretching band originates from induced dipole fluctuations. The use of the self-consistent method enhances the intensity of the stretching peak relative to a non-iterative method, producing improved agreement with experiment. The frequency of the librational band is influenced significantly by long-range electrostatic interactions in the potential function. In contrast, the induced dipole fluctuations are relatively insensitive to the long-range effects; the effective isotropy of the molecular polarizability tensor is found to lead to a decoupling of the induced dipole fluctuations from the dynamical intermolecular orientational correlations of the permanent dipoles. [ABSTRACT FROM AUTHOR]