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“Water, water everywhere…” from amyloid fibrils to influenza A virus channels,
water molecules are recognized by their fluctuating interactions with chemical
bonds by the new 2D infrared methods
A. Gosh1, Y.-S. Kim1, J. Qiu3, L. Liu2, R. DeVane4, T. Troxler1, W. F. DeGrado3, P. H. Axelsen2, and R. M. Hochstrasser1
1Department of Chemistry, 2Department of Pharmacology, 3Department of Biochemistry and Biophysics, and 4Center for Molecular Modeling, University of Pennsylvania, Philadelphia, PA 19104.
Ultrafast Optical Processes Laboratory
Two-dimensional infrared (2D IR) combines the time resolution of ultrafast lasers with the structural
sensitivity of IR spectroscopy, capable of gaining insight into the interaction between structural regions
through their bond correlation functions and structural features. The Resource is advancing the
technology of such experiments making them more accessible to answering questions in complex
biological systems. New probes involving isotopic and chemical replacement techniques to enable direct
experimental investigations of local interactions even in very large systems are being developed. Two
related research projects are shown in this poster. In the first, based on earlier 2D IR analysis of amyloid
fibrils (1), we show the novel and unexpected result that the fibrils from Alzheimer’s disease contain water
channels whose location on strands is clearly identified (2). In the second we present a new direct
identification of the properties of the water at various locations across the trans-membrane portion of the
M2 channel of the Influenza A virus. Both projects involve new laser technology, new probe techniques,
detailed theoretical processing developments and analysis, and collaborations between the Resource and
forefront biophysics research groups.
An atomic scale description of protein aggregation is a great challenge for biophysics. One such process
is the formation of amyloid plaques in Alzheimer’s disease. Here, 2D IR experiments on Aβ40 show that there are water channels in the fibrils whose spatial locations were deduced from responses of 18 13C=18O-labeled amides. Fast frequency variations were found for L17 and V18 and for the apposed residues L34 and V36 suggesting a water channel can form between the two sheets. There are 1.2 water molecules per
strand in the fibrils. One 13C=18O substitution creates a linear array of isotopologues along the fibril axis that manifests highly recognizable vibrational transitions. Here, the distributions of amide-I′ vibrational frequencies show that the regularity of these chains is strongly residue dependent and in most cases the distorted regions are those associated with nearby mobile water molecules. It is proposed that Aβ40 fibrils contain structurally significant mobile water molecules within an inter-sheet region as illustrated by the shaded regions in Figure 1.
Infection by the Influenza A virus is a continuing human health issue, which had been addressed by vaccines that included drugs targeting the M2 proton channel, but the widespread transmission of amantadine-resistant strains of influenza did away with their use. There is a medical need to understand the microscopic mechanism of action of the previously effective prototype M2 proton channel inhibitor and define how mutants can escape inhibition, thereby contributing to the design of inhibitors that target amantadine-resistant forms of M2. The M2 protein has transmembrane helices which associate to form a homotetrameric channel: it is a proton conductor at low pH. Our experiments probe the associated water within the M2 proton channel of the Influenza A virus and its operational mechanism under different pH conditions by means of 13C=18O (Figure 2) and nitrile probes associated with glycines and tryptophans that sense the structure of the water at various locations along the channel.
(1) Kim YS, Liu L, Axelsen PH, Hochstrasser RM. 2008 "Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Aβ40", Proc. Natl. Acad. Sci. USA 105(22):7720-7725. (2) Kim YS, Liu L, Axelsen PH, Hochstrasser RM. 2009 "2D IR reveals mobile water molecules in β-amyloid fibrils", Proc. Natl. Acad. Sci. USA (in press).
FURTHER REVELATIONS by C.Lovell. INTRODUCTION. Most of the information in this paper has not been easy to obtain, and much of it is sensitive. In most casesthe sources of information have been indicated by a code; refer to the last sheet for the bibliography andcodes. All statements have been made in good faith, but it is possible that some of the reference books arenow out of date, or that
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