792 research outputs found
Role of the Subunits Interactions in the Conformational Transitions in Adult Human Hemoglobin: an Explicit Solvent Molecular Dynamics Study
Hemoglobin exhibits allosteric structural changes upon ligand binding due to
the dynamic interactions between the ligand binding sites, the amino acids
residues and some other solutes present under physiological conditions. In the
present study, the dynamical and quaternary structural changes occurring in two
unligated (deoxy-) T structures, and two fully ligated (oxy-) R, R2 structures
of adult human hemoglobin were investigated with molecular dynamics. It is
shown that, in the sub-microsecond time scale, there is no marked difference in
the global dynamics of the amino acids residues in both the oxy- and the deoxy-
forms of the individual structures. In addition, the R, R2 are relatively
stable and do not present quaternary conformational changes within the time
scale of our simulations while the T structure is dynamically more flexible and
exhibited the T\rightarrow R quaternary conformational transition, which is
propagated by the relative rotation of the residues at the {\alpha}1{\beta}2
and {\alpha}2{\beta}1 interface.Comment: Reprinted (adapted) with permission from J. Phys. Chem. B
DOI:10.1021/jp3022908. Copyright (2012) American Chemical Societ
The variability of nitro group-protein interaction in the 2,4-dinitrophenyl-binding antibodies M315, M460 and X25 investigated by resonance Raman spectroscopy
Improving the photocatalytic reduction of CO2 to CO through immobilisation of a molecular Re catalyst on TiO2.
The photocatalytic activity of phosphonated Re complexes, [Re(2,2'-bipyridine-4,4'-bisphosphonic acid) (CO)3(L)] (ReP; L = 3-picoline or bromide) immobilised on TiO2 nanoparticles is reported. The heterogenised Re catalyst on the semiconductor, ReP-TiO2 hybrid, displays an improvement in CO2 reduction photocatalysis. A high turnover number (TON) of 48 molCO molRe(-1) is observed in DMF with the electron donor triethanolamine at λ>420 nm. ReP-TiO2 compares favourably to previously reported homogeneous systems and is the highest TON reported to date for a CO2-reducing Re photocatalyst under visible light irradiation. Photocatalytic CO2 reduction is even observed with ReP-TiO2 at wavelengths of λ>495 nm. Infrared and X-ray photoelectron spectroscopies confirm that an intact ReP catalyst is present on the TiO2 surface before and during catalysis. Transient absorption spectroscopy suggests that the high activity upon heterogenisation is due to an increase in the lifetime of the immobilised anionic Re intermediate (t50% >1 s for ReP-TiO2 compared with t50% = 60 ms for ReP in solution) and immobilisation might also reduce the formation of inactive Re dimers. This study demonstrates that the activity of a homogeneous photocatalyst can be improved through immobilisation on a metal oxide surface by favourably modifying its photochemical kinetics.Financial support from the EPSRC (EP/H00338X/2 to E.R.; studentship and Doctoral
Prize to C.D.W.; DTP scholarship to E.P.), the Christian Doppler Research
Association (Austrian Federal Ministry of Science, Research and Economy and the
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National Foundation for Research, Technology and Development) and the OMV
Group (to E.R.), the ERC (project Intersolar to J.D.) and the European Commission
Marie Curie CIG (PCIG10-GA-2011-303650 to A.R.) is gratefully acknowledged.This is the final published version. It first appeared in Chemistry - a European Journal, 2015, 21, 3746 – 3754, DOI: 10.1002/chem.20140504
Kinetics of stochastically-gated diffusion-limited reactions and geometry of random walk trajectories
In this paper we study the kinetics of diffusion-limited, pseudo-first-order
A + B -> B reactions in situations in which the particles' intrinsic
reactivities vary randomly in time. That is, we suppose that the particles are
bearing "gates" which interchange randomly and independently of each other
between two states - an active state, when the reaction may take place, and a
blocked state, when the reaction is completly inhibited. We consider four
different models, such that the A particle can be either mobile or immobile,
gated or ungated, as well as ungated or gated B particles can be fixed at
random positions or move randomly. All models are formulated on a
-dimensional regular lattice and we suppose that the mobile species perform
independent, homogeneous, discrete-time lattice random walks. The model
involving a single, immobile, ungated target A and a concentration of mobile,
gated B particles is solved exactly. For the remaining three models we
determine exactly, in form of rigorous lower and upper bounds, the large-N
asymptotical behavior of the A particle survival probability. We also realize
that for all four models studied here such a probalibity can be interpreted as
the moment generating function of some functionals of random walk trajectories,
such as, e.g., the number of self-intersections, the number of sites visited
exactly a given number of times, "residence time" on a random array of lattice
sites and etc. Our results thus apply to the asymptotical behavior of the
corresponding generating functions which has not been known as yet.Comment: Latex, 45 pages, 5 ps-figures, submitted to PR
Academic freedom: in justification of a universal ideal
This paper examines the justification for, and benefits of, academic freedom to academics, students, universities and the world at large. The paper surveys the development of the concept of academic freedom within Europe, more especially the impact of the reforms at the University of Berlin instigated by Wilhelm von Humboldt. Following from this, the paper examines the reasons why the various facets of academic freedom are important and why the principle should continue to be supported
Deciphering the Structure, Growth and Assembly of Amyloid-Like Fibrils Using High-Speed Atomic Force Microscopy
Formation of fibrillar structures of proteins that deposit into aggregates has been suggested to play a key role in various neurodegenerative diseases. However mechanisms and dynamics of fibrillization remains to be elucidated. We have previously established that lithostathine, a protein overexpressed in the pre-clinical stages of Alzheimer's disease and present in the pathognomonic lesions associated with this disease, form fibrillar aggregates after its N-terminal truncation. In this paper we visualized, using high-speed atomic force microscopy (HS-AFM), growth and assembly of lithostathine protofibrils under physiological conditions with a time resolution of one image/s. Real-time imaging highlighted a very high velocity of elongation. Formation of fibrils via protofibril lateral association and stacking was also monitored revealing a zipper-like mechanism of association. We also demonstrate that, like other amyloid ß peptides, two lithostathine protofibrils can associate to form helical fibrils. Another striking finding is the propensity of the end of a growing protofibril or fibril to associate with the edge of a second fibril, forming false branching point. Taken together this study provides new clues about fibrillization mechanism of amyloid proteins
Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations
Polyglutamine (polyQ) beta-stranded aggregates constitute the hallmark of Huntington disease. The disease is fully penetrant when Q residues are more than 36-40 ("disease threshold"). Here, based on a molecular dynamics study on polyQ helical structures of different shapes and oligomeric states, we suggest that the stability of the aggregates increases with the number of monomers, while it is rather insensitive to the number of Qs in each monomer. However, the stability of the single monomer does depend on the number of side-chain intramolecular H-bonds, and therefore oil the number of Qs. If such number is lower than that of the disease threshold, the beta-stranded monomers are unstable and hence may aggregate with lower probability, consistently with experimental findings. Our results provide a possible interpretation of the apparent polyQ length dependent-toxicity, and they do not support the so-called "structural threshold hypothesis", which supposes a transition from random coil to a beta-sheet structure only above the disease threshold
Role of water in Protein Aggregation and Amyloid Polymorphism
A variety of neurodegenerative diseases are associated with the formation of
amyloid plaques. Our incomplete understanding of this process underscores the
need to decipher the principles governing protein aggregation. Most
experimental and simulation studies have been interpreted largely from the
perspective of proteins: the role of solvent has been relatively overlooked.
In this Account, we provide a perspective on how interactions with water
affect folding landscapes of A monomers, A oligomer
formation, and protofilament formation in a Sup35 peptide. Simulations show
that the formation of aggregation-prone structures (N) similar to the
structure in the fibril requires overcoming high desolvation barrier. The
mechanism of protofilament formation in a polar Sup35 peptide fragment
illustrates that water dramatically slows down self-assembly. Release of water
trapped in the pores as water wires creates protofilament with a dry interface.
Similarly, one of the main driving force for addition of a solvated monomer to
a preformed fibril is the entropy gain of released water.
We conclude by postulating that two-step model for protein crystallization
must also hold for higher order amyloid structure formation starting from
N. Multiple N structures with varying water content results in a number
of distinct water-laden polymorphic structures. In predominantly hydrophobic
sequences, water accelerates fibril formation. In contrast, water-stabilized
metastable intermediates dramatically slow down fibril growth rates in
hydrophilic sequences.Comment: 27 pages, 4 figures; Accounts of Chemical Research, 201
Metal Hydrides Form Halogen Bonds: Measurement of Energetics of Binding
The formation of halogen bonds from iodopentafluorobenzene and 1-iodoperfluorohexane to a series of bis(η5-cyclopentadienyl)metal hydrides (Cp2TaH3, 1; Cp2MH2, M = Mo, 2, M = W, 3; Cp2ReH, 4; Cp2Ta(H)CO, 5; Cp = η5-cyclopentadienyl) is demonstrated by 1H NMR spectroscopy. Interaction enthalpies and entropies for complex 1 with C6F5I and C6F13I are reported (ΔH° = −10.9 ± 0.4 and −11.8 ± 0.3 kJ/mol; ΔS° = −38 ± 2 and −34 ± 2 J/(mol·K), respectively) and found to be stronger than those for 1 with the hydrogen-bond donor indole (ΔH° = −7.3 ± 0.1 kJ/mol, ΔS° = −24 ± 1 J/(mol·K)). For the more reactive complexes 2–5, measurements are limited to determination of their low-temperature (212 K) association constants with C6F5I as 2.9 ± 0.2, 2.5 ± 0.1, <1.5, and 12.5 ± 0.3 M–1, respectively
Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences
Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation
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