233 research outputs found
Anharmonicity and self-similarity of the free energy landscape of protein G
The near-native free energy landscape of protein G is investigated through
0.4 microseconds-long atomistic molecular dynamics simulations in explicit
solvent. A theoretical and computational framework is used to assess the
time-dependence of salient thermodynamical features. While the quasi-harmonic
character of the free energy is found to degrade in a few ns, the slow modes
display a very mild dependence on the trajectory duration. This property
originates from a striking self-similarity of the free energy landscape
embodied by the consistency of the principal directions of the local minima,
where the system dwells for several ns, and of the virtual jumps connecting
them.Comment: revtex, 6 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
Cloud computing—effect of evolutionary algorithm on load balancing
© Springer International Publishing Switzerland 2015 In cloud computing due to the multi-tenancy of the resources, there is an essential need for effective load management to ensure an efficient load sharing. Depends on the structure of the tasks, different algorithms could be applied to distribute the load. Workflow scheduling as one of those load distribution algorithms, is specifically designed to schedule the dependent tasks on available resources. Considering a job as an elastic network of dependent tasks, this paper describes how evolutionary algorithm, with its mathematical apparatus, could be applied as workflow scheduling in cloud computing. In this research, the impact of Generalized Spring Tensor Model on workflow load balancing, in context of mathematical patterns have been studied. This research can establish patterns in cloud computing which can be applied in designing the heuristic workflow load balancing algorithms to identify the load patterns of the cloud network. Furthermore, the outcome of this research can help the end users to recognize the threats of tasks failure in processing the e-business and e-since data in cloud environment
Universal behavior of localization of residue fluctuations in globular proteins
Localization properties of residue fluctuations in globular proteins are
studied theoretically by using the Gaussian network model. Participation ratio
for each residue fluctuation mode is calculated. It is found that the
relationship between participation ratio and frequency is similar for all
globular proteins, indicating a universal behavior in spite of their different
size, shape, and architecture.Comment: 4 pages, 3 figures. To appear in Phys. Rev.
Experimental investigation of relationship between trauma and bisphosphonate-related osteonecrosis
Background: Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) disease is rare, but there are serious side-effects of BP therapy in patients. In some patients, surgery is needed and could not be cured. Astandard test is not available showing the risk of jaw osteonecrosis in routine use. The measurement of serum C.terminal telopeptide (CTX) levels has been used in diseases of BRONJ resorption and antiresorptive therapy.Aim: This paper is aimed at investigating the relationship between traumatic procedures and presence of BP-related osteonecrosis.Materials and Methods: Thirty male Wistar albino rats with weighing 200 } 20 g were used for the experimental procedures. Rats were randomly divided into three groups each containing 10 rats as follows: Group 1 (traumatic extraction group), Group 2 (atraumatic extraction group), and Group 3 (control group). All groups, zoledronic acid (ZA) (0.3 mg/kg/week)[1] was diluted with physiological saline and given subcutaneously for 2 months. After the 2 months, Group 1 was subjected totraumatic extraction of right first lower molars, and Group 2 was subjected to atraumatic extractions of the right first lower molars. Group 3 was subjected to no extractions as a control group. Animals were euthanized 32 days after tooth extractions, and the ZA administration protocol was maintained until the animalsf death. After sacrifice, blood samples were collected for C-terminal cross.linking telopeptide of type I collagen (CTX.1) levels, clinical and radiological findings were recorded.Results: The bone resorption marker CTX-1 showed a significant difference among the groups. CTX-1 was measured significantly higher in blood samples of Group 2 (4.15 } 0.34; P = 0.001) than Group 1 (3.77 } 0.34; P = 0.0001). No, statistically significant changes were found between Groups 1 and 2 as for clinical and radiological assessment.Conclusion: This study provides preliminary observations for the development of an animal model of BRONJ. Although clinical and radiological findings were not relevant, serum CTX values are reliable biochemical markers for predicting BRONJ and also atraumatic surgical procedures are important to prevent BRONJ.Key words: Bisphosphonates, bone, osteonecrosis, prevention, serum C-terminal telopeptide leve
Influence of conformational fluctuations on enzymatic activity: modelling the functional motion of beta-secretase
Considerable insight into the functional activity of proteins and enzymes can
be obtained by studying the low-energy conformational distortions that the
biopolymer can sustain. We carry out the characterization of these large scale
structural changes for a protein of considerable pharmaceutical interest, the
human -secretase. Starting from the crystallographic structure of the
protein, we use the recently introduced beta-Gaussian model to identify, with
negligible computational expenditure, the most significant distortion occurring
in thermal equilibrium and the associated time scales. The application of this
strategy allows to gain considerable insight into the putative functional
movements and, furthermore, helps to identify a handful of key regions in the
protein which have an important mechanical influence on the enzymatic activity
despite being spatially distant from the active site. The results obtained
within the Gaussian model are validated through an extensive comparison against
an all-atom Molecular Dynamics simulation.Comment: To be published in a special issue of J. Phys.: Cond. Mat. (Bedlewo
Workshop
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
Solid-state emissive BODIPY dyes with bulky substituents as spacers
Bright fluorescence of the BODIPY dyes, just like most other fluorophores, is quenched in the solid state due to reabsorption and self-quenching. However, introduction of bulky ferf-butyl substituents on the meso-phenyl groups result in more spaced packing in the solid state, resulting in highly luminescent powders and films. © 2009 American Chemical Society
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
2.20.2 mM which is in remarkable agreement with the experimentally
measured value of 2.30.3 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
Resistance distance, information centrality, node vulnerability and vibrations in complex networks
We discuss three seemingly unrelated quantities that have been introduced in different fields of science for complex networks. The three quantities are the resistance distance, the information centrality and the node displacement. We first prove various relations among them. Then we focus on the node displacement, showing its usefulness as an index of node vulnerability.We argue that the node displacement has a better resolution as a measure of node vulnerability than the degree and the information centrality
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