Depth dependent dynamics in the hydration shell of a protein

We study the dynamics of hydration water/protein association in folded proteins, using lysozyme and myoglobin as examples. Extensive molecular dynamics simulations are performed to identify underlying mechanisms of the dynamical transition that corresponds to the onset of amplified atomic fluctuations in proteins. The number of water molecules within a cutoff distance of each residue scales linearly with protein depth index and is not affected by the local dynamics of the backbone. Keeping track of the water molecules within the cutoff sphere, we observe an effective residence time, scaling inversely with depth index at physiological temperatures while the diffusive escape is highly reduced below the transition. A depth independent orientational memory loss is obtained for the average dipole vector of the water molecules within the sphere when the protein is functional. While below the transition temperature, the solvent is in a glassy state, acting as a solid crust around the protein, inhibiting any large scale conformational fluctuations. At the transition, most of the hydration shell unfreezes and water molecules collectively make the protein more flexible.Comment: Journal of Chemical Physics in pres

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

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

XML retrieval using pruned element-index files

An element-index is a crucial mechanism for supporting content-only (CO) queries over XML collections. A full element-index that indexes each element along with the content of its descendants involves a high redundancy and reduces query processing efficiency. A direct index, on the other hand, only indexes the content that is directly under each element and disregards the descendants. This results in a smaller index, but possibly in return to some reduction in system effectiveness. In this paper, we propose using static index pruning techniques for obtaining more compact index files that can still result in comparable retrieval performance to that of a full index. We also compare the retrieval performance of these pruning based approaches to some other strategies that make use of a direct element-index. Our experiments conducted along with the lines of INEX evaluation framework reveal that pruned index files yield comparable to or even better retrieval performance than the full index and direct index, for several tasks in the ad hoc track. © 2010 Springer-Verlag Berlin Heidelberg

Exploiting index pruning methods for clustering XML collections

In this paper, we first employ the well known Cover-Coefficient Based Clustering Methodology (C3M) for clustering XML documents. Next, we apply index pruning techniques from the literature to reduce the size of the document vectors. Our experiments show that for certain cases, it is possible to prune up to 70% of the collection (or, more specifically, underlying document vectors) and still generate a clustering structure that yields the same quality with that of the original collection, in terms of a set of evaluation metrics. © 2010 Springer-Verlag Berlin Heidelberg

On the size of full element-indexes for XML keyword search

We show that a full element-index can be as space-efficient as a direct index with Dewey ids, after compression using typical techniques. © 2012 Springer-Verlag Berlin Heidelberg

Protonation States of Remote Residues Affect Binding-Release Dynamics of the Ligand but not the Conformation of apo Ferric Binding Protein

We have studied the apo (Fe3+ free) form of periplasmic ferric binding protein (FbpA) under different conditions and we have monitored the changes in the binding and release dynamics of H2PO4- that acts as a synergistic anion in the presence of Fe3+. Our simulations predict a dissociation constant of 2.2$\pm$0.2 mM which is in remarkable agreement with the experimentally measured value of 2.3$\pm$0.3 mM under the same ionization strength and pH conditions. We apply perturbations relevant for changes in environmental conditions as (i) different values of ionic strength (IS), and (ii) protonation of a group of residues to mimic a different pH environment. Local perturbations are also studied by protonation or mutation of a site distal to the binding region that is known to mechanically manipulate the hinge-like motions of FbpA. We find that while the average conformation of the protein is intact in all simulations, the H2PO4- dynamics may be substantially altered by the changing conditions. In particular, the bound fraction which is 20$\%$ for the wild type system is increased to 50$\%$ with a D52A mutation/protonation and further to over 90$\%$ at the protonation conditions mimicking those at pH 5.5. The change in the dynamics is traced to the altered electrostatic distribution on the surface of the protein which in turn affects hydrogen bonding patterns at the active site. The observations are quantified by rigorous free energy calculations. Our results lend clues as to how the environment versus single residue perturbations may be utilized for regulation of binding modes in hFbpA systems in the absence of conformational changes.Comment: 26 pages, 4 figure

A geometrically nonlinear theory of elastic plates

equations follow. It is shown that only five equilibrium equations can be derived in this manner, because the component of virtual rotation about the normal is not independent. These equilibrium equations contain terms which cannot be obtained without the use of a finite rotation vector which contains three nonzero components. These extra terms correspond to the difference of in-plane shear stress resultants in other theories; this difference is a reactive quantity in the present theory. Introduction This paper focuses on geometrically nonlinear analysis (i.e., small strain with possibly large deflections and rotations) of plates-solids with one small dimension and without initial curvature. We note that if all three dimensions of a flexible body are comparable, and if the body is undergoing smallstrain deformation, then the displacement field in addition to rigid-body motion must be small. If, however, one or two dimensions of the body are small relative to the other(s), then even if the strains remain small the body can undergo large deflections

Perturbation-Response Scanning Reveals Ligand Entry-Exit Mechanisms of Ferric Binding Protein

We study apo and holo forms of the bacterial ferric binding protein (FBP) which exhibits the so-called ferric transport dilemma: it uptakes iron from the host with remarkable affinity, yet releases it with ease in the cytoplasm for subsequent use. The observations fit the “conformational selection” model whereby the existence of a weakly populated, higher energy conformation that is stabilized in the presence of the ligand is proposed. We introduce a new tool that we term perturbation-response scanning (PRS) for the analysis of remote control strategies utilized. The approach relies on the systematic use of computational perturbation/response techniques based on linear response theory, by sequentially applying directed forces on single-residues along the chain and recording the resulting relative changes in the residue coordinates. We further obtain closed-form expressions for the magnitude and the directionality of the response. Using PRS, we study the ligand release mechanisms of FBP and support the findings by molecular dynamics simulations. We find that the residue-by-residue displacements between the apo and the holo forms, as determined from the X-ray structures, are faithfully reproduced by perturbations applied on the majority of the residues of the apo form. However, once the stabilizing ligand (Fe) is integrated to the system in holo FBP, perturbing only a few select residues successfully reproduces the experimental displacements. Thus, iron uptake by FBP is a favored process in the fluctuating environment of the protein, whereas iron release is controlled by mechanisms including chelation and allostery. The directional analysis that we implement in the PRS methodology implicates the latter mechanism by leading to a few distant, charged, and exposed loop residues. Upon perturbing these, irrespective of the direction of the operating forces, we find that the cap residues involved in iron release are made to operate coherently, facilitating release of the ion