440 research outputs found
Subtle pH differences trigger single residue motions for moderating conformations of calmodulin
This study reveals the essence of ligand recognition mechanisms by which calmodulin (CaM) controls a variety of Ca2+ signaling processes. We study eight forms of calcium-loaded CaM each with distinct conformational states. Reducing the structure to two degrees of freedom conveniently describes main features of the conformational changes of CaM via simultaneous twist-bend motions of the two lobes. We utilize perturbation-response scanning (PRS) technique, coupled with molecular dynamics simulations. PRS is based on linear response theory, comprising sequential application of directed forces on selected residues followed by recording the resulting protein coordinates. We analyze directional preferences of the perturbations and resulting conformational changes. Manipulation of a single residue reproduces the structural change more effectively than that of single/pairs/triplets of collective modes of motion. Our findings also give information on how the flexible linker acts as a transducer of binding information to distant parts of the protein. Furthermore, by perturbing residue E31 located in one of the EF hand motifs in a specific direction, it is possible to induce conformational change relevant to five target structures. Independently, using four different pKa calculation strategies, we find this particular residue to be the charged residue (out of a total of 52), whose ionization state is most sensitive to subtle pH variations in the physiological range. It is plausible that at relatively low pH, CaM structure is less flexible. By gaining charged states at specific sites at a pH value around 7, such as E31 found in the present study, local conformational changes in the protein will lead to shifts in the energy landscape, paving the way to other conformational states. These findings are in accordance with Fluorescence Resonance Energy Transfer (FRET) measured shifts in conformational distributions towards more compact forms with decreased pH. They also corroborate mutational studies and proteolysis results which point to the significant role of E31 in CaM dynamics
Renal cell carcinoma with concomitant solid pseudopapillary tumor of the pancreas: A case report
AbstractINTRODUCTIONSolid pseudopapillary tumor (SPT) of pancreas is an unusual low-grade malignant epithelial tumor that usually occurs in young women and can be treated with surgical resection. Renal cell carcinoma (RCC) is the most common solid lesion of the kidney and primarily a disease of the elderly patient.PRESENTATION OF CASEIn this article we present a case of RCC with concomitant SPT of the pancreas who was treated successfully with a radical nephrectomy and distal pancreatectomy.DISCUSSIONRCC with concomitant SPT may associated in β-catenin gene mutation. But no prior reports have described RCC with concomitant SPT of the pancreas in the same patient.CONCLUSIONTo the best of our knowledge, this is the first report of RCC with concomitant SPT of the pancreas in the same patient
Functional modes of proteins are among the most robust ones
It is shown that a small subset of modes which are likely to be involved in
protein functional motions of large amplitude can be determined by retaining
the most robust normal modes obtained using different protein models. This
result should prove helpful in the context of several applications proposed
recently, like for solving difficult molecular replacement problems or for
fitting atomic structures into low-resolution electron density maps. Moreover,
it may also pave the way for the development of methods allowing to predict
such motions accurately.Comment: 4 pages, 5 figure
Driving calmodulin protein towards conformational shift by changing ionization states of select residues
Proteins are complex systems made up of many conformational sub-states which are mainly determined by the folded structure. External factors such as solvent type, temperature, pH and ionic strength play a very important role in the conformations sampled by proteins. Here we study the conformational multiplicity of calmodulin (CaM) which is a protein that plays an important role in calcium signaling pathways in the eukaryotic cells. CaM can bind to a variety of other proteins or small organic compounds, and mediates different physiological processes by activating various enzymes. Binding of calcium ions and proteins or small organic molecules to CaM induces large conformational changes that are distinct to each interacting partner. In particular, we discuss the effect of pH variation on the conformations of CaM. By using the pKa values of the charged residues as a basis to assign protonation states, the conformational changes induced in CaM by reducing the pH are studied by molecular dynamics simulations. Our current view suggests that at high pH, barrier crossing to the compact form is prevented by repulsive electrostatic interactions between the two lobes. At reduced pH, not only is barrier crossing facilitated by protonation of residues, but also conformations which are on average more compact are attained. The latter are in accordance with the fluorescence resonance energy transfer experiment results of other workers. The key events leading to the conformational change from the open to the compact conformation are (i) formation of a salt bridge between the N-lobe and the linker, stabilizing their relative motions, (ii) bending of the C-lobe towards the N-lobe, leading to a lowering of the interaction energy between the two-lobes, (iii) formation of a hydrophobic patch between the two lobes, further stabilizing the bent conformation by reducing the entropic cost of the compact form, (iv) sharing of a Ca+2 ion between the two lobes
Subtle pH differences trigger single residue motions for moderating conformations of calmodulin
This study reveals the essence of ligand recognition mechanisms by which
calmodulin (CaM) controls a variety of Ca2+ signaling processes. We study eight
forms of calcium-loaded CaM each with distinct conformational states. Reducing
the structure to two degrees of freedom conveniently describes main features of
conformational changes of CaM via simultaneous twist-bend motions of the two
lobes. We utilize perturbation-response scanning (PRS) technique, coupled with
molecular dynamics simulations to analyze conformational preferences of
calcium-loaded CaM, initially in extended form. PRS is comprised of sequential
application of directed forces on residues followed by recording the resulting
coordinates. We show that manipulation of a single residue, E31 located in one
of the EF hand motifs, reproduces structural changes to compact forms, and the
flexible linker acts as a transducer of binding information to distant parts of
the protein. Independently, using four different pKa calculation strategies, we
find E31 to be the charged residue (out of 52), whose ionization state is most
sensitive to subtle pH variations in the physiological range. It is proposed
that at relatively low pH, CaM structure is less flexible. By gaining charged
states at specific sites at a pH value around 7, local conformational changes
in the protein will lead to shifts in the energy landscape, paving the way to
other conformational states. These findings are in accordance with FRET
measured shifts in conformational distributions towards more compact forms with
decreased pH. They also corroborate mutational studies and proteolysis results
which point to the significant role of E31 in CaM dynamics.Comment: 47 pages, 4 figure
A sensitive and selective ratiometric near IR fluorescent probe for zinc ions based on the distyryl-bodipy fluorophore
(Chemical Equation Presented) A novel distyryl-substituted boradiazaindacene (bodipy) dye with an emission peak moving hypsochromically from 730 to 680 nm on Zn(II) ion binding seems to be promising as one of the very few water-soluble fluorescent chemosensors emitting in the near IR region. © 2008 American Chemical Society
Classical, semiclassical, and quantum investigations of the 4-sphere scattering system
A genuinely three-dimensional system, viz. the hyperbolic 4-sphere scattering
system, is investigated with classical, semiclassical, and quantum mechanical
methods at various center-to-center separations of the spheres. The efficiency
and scaling properties of the computations are discussed by comparisons to the
two-dimensional 3-disk system. While in systems with few degrees of freedom
modern quantum calculations are, in general, numerically more efficient than
semiclassical methods, this situation can be reversed with increasing dimension
of the problem. For the 4-sphere system with large separations between the
spheres, we demonstrate the superiority of semiclassical versus quantum
calculations, i.e., semiclassical resonances can easily be obtained even in
energy regions which are unattainable with the currently available quantum
techniques. The 4-sphere system with touching spheres is a challenging problem
for both quantum and semiclassical techniques. Here, semiclassical resonances
are obtained via harmonic inversion of a cross-correlated periodic orbit
signal.Comment: 12 pages, 5 figures, submitted to Phys. Rev.
Selective Hg(II) sensing with improved stokes shift by coupling the internal charge transfer process to excitation energy transfer
Versatile chemistry of the Bodipy chromophore allows modular assembly of an excitation energy donor, acceptor, and a cation selective ligand in just a couple of steps. The new approach should be applicable in other designs which target molecular sensors with large Stokes shifts and red to near IR emission. © 2010 American Chemical Society
Near-IR-Triggered, Remote-Controlled Release of Metal Ions: A Novel Strategy for Caged Ions
Cataloged from PDF version of article.A ligand incorporating a dithioethenyl moiety is cleaved into fragments which have a lower metal-ion affinity upon irradiation with low-energy red/near-IR light. The cleavage is a result of singlet oxygen generation which occurs on excitation of the photosensitizer modules. The method has many tunable factors that could make it a satisfactory caging strategy for metal ions
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