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Helix stabilization

Giuseppe Lanza, Maria A Chiacchio
Exploration of interfacial hydration networks of zwitterion and non-ionized trialanine has been performed using DFT-M062X quantum chemical computations explicitly considering up to 41 water molecules. The step-by-step water molecules peptide surrounding, carried out for unfolded extended (β), polyproline II (PPII) conformations reveals the crucial importance of explicit solvent effects in stabilizing the zwitterion form and the left-handed PPII-helix ubiquitously found at room temperature for short polyalanines...
October 21, 2016: Journal of Physical Chemistry. B
N Bavi, O Bavi, M Vossoughi, R Naghdabadi, A P Hill, B Martinac, Y Jamali
Gating of mechanosentive (MS) channels is driven by a hierarchical cascade of movements and deformations of transmembrane helices in response to bilayer tension. Determining the intrinsic mechanical properties of the individual transmembrane helices is therefore central to understanding the intricacies of the gating mechanism of MS channels. We used a constant-force steered molecular dynamics (SMD) approach to perform unidirectional pulling tests on all the helices of MscL in M. tuberculosis and E. coli homologs...
October 18, 2016: Channels
Annick Renevey, Sereina Riniker
Polytheonamide B (pTB), a highly cytotoxic peptide produced by a symbiotic bacterium of the marine sponge Theonella swinhoei, forms a transmembrane pore consisting of 49 residues. More than half of its residues are posttranslationally modified. Epimerizations result in alternating L- and D-amino acids that allow the peptide to adopt a [Formula: see text]-helical conformation. Unusually, the wide [Formula: see text]-helix of pTB is stable in a polar environment, which is in contrast to gramicidin A, an antibiotic with similar function and structure...
October 15, 2016: European Biophysics Journal: EBJ
Ursula Schulze-Gahmen, Ignacia Echeverria, Goran Stjepanovic, Yun Bai, Huasong Lu, Dina Schneidman-Duhovny, Jennifer A Doudna, Qiang Zhou, Andrej Sali, James H Hurley
HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1. The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn(2+)-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. RNA SHAPE and SAXS data were used to help model the extended (Tat Arginine-Rich Motif) ARM, which enters the TAR major groove between the bulge and the central loop...
October 12, 2016: ELife
Delong Wang, Ken-Ichi Miyazono, Masaru Tanokura
R.PabI is a type II restriction enzyme that recognizes the 5'-GTAC-3' sequence and belongs to the HALFPIPE superfamily. Although most restriction enzymes cleave phosphodiester bonds at specific sites by hydrolysis, R.PabI flips the guanine and adenine bases of the recognition sequence out of the DNA helix and hydrolyzes the N-glycosidic bond of the flipped adenine in a similar manner to DNA glycosylases. In this study, we determined the structure of R.PabI in complex with double-stranded DNA without the R.PabI recognition sequence by X-ray crystallography...
October 12, 2016: Scientific Reports
Petr Jeřábek, Jan Florián, Václav Martínek
Cytochrome P450 1A2 (P450 1A2, CYP1A2) is a membrane-bound enzyme that oxidizes a broad range of hydrophobic substrates. The structure and dynamics of both the catalytic and trans-membrane (TM) domains of this enzyme in the membrane/water environment were investigated using a multiscale computational approach, including coarse-grained and all-atom molecular dynamics. Starting from the spontaneous self-assembly of the system containing the TM or soluble domain immersed in randomized dilauroyl phosphatidylcholine (DLPC)/water mixture into their respective membrane-bound forms, we reconstituted the membrane-bound structure of the full-length P450 1A2...
September 26, 2016: Physical Chemistry Chemical Physics: PCCP
Andrew K Lewis, Christopher C Valley, Stephen L Peery, Benjamin Brummel, Anthony R Braun, Christine Karim, Jonathan N Sachs
Death receptor 5 (DR5) is an apoptosis-inducing member of the tumor necrosis factor superfamily, whose activity has been linked to membrane cholesterol content. Upon ligand binding, DR5 forms large clusters within the plasma membrane that have often been assumed to be manifestations of receptor co-localization in cholesterol-rich membrane domains. However, we have recently shown that DR5 clusters are more than just randomly aggregated receptors. Instead, these are highly structured networks held together by receptor dimers...
October 6, 2016: Journal of Molecular Biology
Takahiro Shimada, Le Van Lich, Koyo Nagano, Jian-Shan Wang, Jie Wang, Takayuki Kitamura
Topological objects of nontrivial spin or dipolar field textures, such as skyrmions, merons, and vortices, interacting with applied external fields in ferroic materials are of great scientific interest as an intriguing playground of unique physical phenomena and novel technological paradigms. The quest for new topological configurations of such swirling field textures has primarily been done for magnets with Dzyaloshinskii-Moriya interactions, while the absence of such intrinsic chiral interactions among electric dipoles left ferroelectrics aside in this quest...
October 7, 2016: Scientific Reports
Joseph R Gord, Daniel M Hewett, Alicia O Hernandez-Castillo, Karl N Blodgett, Matthew C Rotondaro, Adalgisa Varuolo, Matthew A Kubasik, Timothy S Zwier
The conformational preferences of a series of capped peptides containing the helicogenic amino acid aminoisobutyric acid (Aib) (Z-Aib-OH, Z-(Aib)2-OMe, and Z-(Aib)4-OMe) are studied in the gas phase under expansion-cooled conditions. Aib oligomers are known to form 310-helical secondary structures in solution and in the solid phase. However, in the gas phase, accumulation of a macrodipole as the helix grows could inhibit helix stabilization. Implementing single-conformation IR spectroscopy in the NH stretch region, Z-Aib-OH and Z-(Aib)2-OMe are both observed to have minor conformations that exhibit dihedral angles consistent with the 310-helical portion of the Ramachandran map (ϕ, ψ = -57°, -30°), even though they lack sufficient backbone length to form 10-membered rings which are a hallmark of the developed 310-helix...
September 14, 2016: Physical Chemistry Chemical Physics: PCCP
Avik Samanta, Zhichang Liu, Siva Krishna Mohan Nalluri, Yu Zhang, George C Schatz, James Fraser Stoddart
Solid-state superstructures, resulting from assemblies programmed by homochirality are attracting considerable attention. In addition, artificial double-helical architectures are being investigated, especially in relation to the ways in which homochiral small molecules can be induced to yield helical forms as a result of chiral induction. Herein, we report the highly specific self-assembly upon crystallization of a double helical superstructure from an enantiopure macrocyclic dimer which adopts two diastereoisomeric conformations in a molar ratio of 1...
October 6, 2016: Journal of the American Chemical Society
Lijia Liu, Naoki Ousaka, Miki Horie, Fumihiko Mamiya, Eiji Yashima
A preferred-handed helicity induced in an optically-inactive poly(phenyleneethynylene)-based foldamer bearing carboxylic acid pendants upon complexation with a single enantiomeric diamine was subsequently inverted into the opposite helix upon further addition of the diamine, accompanied by a remarkable change in the stability of the helices.
September 27, 2016: Chemical Communications: Chem Comm
Hanting Yang, Miaohui Hu, Jianli Guo, Xiaomin Ou, Tanxi Cai, Zhenfeng Liu
Intracellular Ca(2+) signalling processes are fundamental to muscle contraction, neurotransmitter release, cell growth and apoptosis. Release of Ca(2+) from the intracellular stores is supported by a series of ion channels in sarcoplasmic or endoplasmic reticulum (SR/ER). Among them, two isoforms of the trimeric intracellular cation (TRIC) channel family, named TRIC-A and TRIC-B, modulate the release of Ca(2+) through the ryanodine receptor or inositol triphosphate receptor, and maintain the homeostasis of ions within SR/ER lumen...
October 3, 2016: Nature
Weihua Zheng, Min-Yeh Tsai, Mingchen Chen, Peter G Wolynes
A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1-40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Jianzhong Chen
Extracellular signal-regulated kinase 2 (ERK2) is a promising target for designs and development of anticancer drugs. Molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann method were applied to study binding difference of ADP and ATP to ERK2. The results prove that the binding ability of ATP to ERK2 is stronger than that of ADP. Principal component analysis performed by using MD trajectories suggest that bindings of ADP and ATP to ERK2 change motion directions of two helixes α1 and α2...
October 3, 2016: Chemical Biology & Drug Design
M Hunter Giese, Alison Gardner, Angela Hansen, Michael C Sanguinetti
Large conductance K(+) -selective Slo2 channels are in a closed state unless activated by elevated [Na(+) ]i . Our previous studies suggested that the pore helix/selectivity filter serves as the activation gate in Slo2 channels. Here we evaluate two other potential mechanisms for stabilization of Slo2 channels in a closed state: 1) dewetting and collapse of the inner pore (hydrophobic gating), and 2) constriction of the inner pore by tight criss-crossing of the cytoplasmic ends of the S6 α-helical segments...
September 28, 2016: Journal of Physiology
Pradeep Sathyanarayana, Rajat Desikan, K Ganapathy Ayappa, Sandhya S Visweswariah
Pore-forming toxins (PFTs) bind to cell membranes and form nanoscale pores that allow leakage of cellular components, resulting in cell death. The water-soluble, monomeric form of these toxins shows a dramatic conformational change during pore formation, as exemplified by crystal structures of the monomer and functional pore of cytolysin A (ClyA). The solvent-exposed, C-terminal residues of the protein are essential for activity, but the mechanism by which this region regulates pore formation remains unknown...
October 13, 2016: Biochemistry
Axel Schmidt, Daniel Löhrer, Richard J Alsop, Pia Lenzig, Adrienne Oslender-Bujotzek, Monika Wirtz, Maikel C Rheinstädter, Stefan Gründer, Dominik Wiemuth
The bile acid-sensitive ion channel (BASIC) is a member of the Deg/ENaC family of ion channels. It is mainly found in bile duct epithelial cells, the intestinal tract and the cerebellum and activated by alterations of its membrane environment. Bile acids, one class of putative physiological activators, exert their effect by changing membrane properties, leading to an opening of the channel. The physiological function of BASIC, however, is unknown. Deg/ENaC channels are characterized by a trimeric subunit composition...
September 27, 2016: Journal of Biological Chemistry
Karl V Gorzelnik, Zhicheng Cui, Catrina A Reed, Joanita Jakana, Ry Young, Junjie Zhang
Single-stranded (ss) RNA viruses infect all domains of life. To date, for most ssRNA virions, only the structures of the capsids and their associated protein components have been resolved to high resolution. Qβ, an ssRNA phage specific for the conjugative F-pilus, has a T = 3 icosahedral lattice of coat proteins assembled around its 4,217 nucleotides of genomic RNA (gRNA). In the mature virion, the maturation protein, A2, binds to the gRNA and is required for adsorption to the F-pilus. Here, we report the cryo-electron microscopy (cryo-EM) structures of Qβ with and without symmetry applied...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yun Zhu, Shan Su, Lili Qin, Qian Wang, Lei Shi, Zhenxuan Ma, Jianchao Tang, Shibo Jiang, Lu Lu, Sheng Ye, Rongguang Zhang
Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL...
September 26, 2016: Scientific Reports
Alan J Waring, Monik Gupta, Larry M Gordon, Gary Fujii, Frans J Walther
Surfactant protein B (SP-B; 79 residues) is a member of the saposin superfamily and plays a pivotal role in lung function. The N- and C-terminal regions of SP-B, cross-linked by two disulfides, were theoretically predicted to fold as charged amphipathic helices, suggesting participation in surfactant activities. Previous studies with oxidized Super Mini-B (SMB), a construct based on the N- and C-regions of SP-B (i.e., residues 1-25 and 63-78) joined with a designer turn (-PKGG-) and two disulfides, indicated that freshly prepared SMB in lipids folded as a surface active, α-helix-hairpin...
September 21, 2016: Biochimica et Biophysica Acta
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