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

On the origin of the Boson peak in globular proteins

We study the Boson Peak phenomenology experimentally observed in globular proteins by means of elastic network models. These models are suitable for an analytic treatment in the framework of Euclidean Random Matrix theory, whose predictions can be numerically tested on real proteins structures. We find that the emergence of the Boson Peak is strictly related to an intrinsic mechanical instability of the protein, in close similarity to what is thought to happen in glasses. The biological implications of this conclusion are also discussed by focusing on a representative case study.Comment: Proceedings of the X International Workshop on Disordered Systems, Molveno (2006

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

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

On the conservation of the slow conformational dynamics within the amino acid kinase family: NAGK the paradigm

N-Acetyl-L-Glutamate Kinase (NAGK) is the structural paradigm for examining the catalytic mechanisms and dynamics of amino acid kinase family members. Given that the slow conformational dynamics of the NAGK (at the microseconds time scale or slower) may be rate-limiting, it is of importance to assess the mechanisms of the most cooperative modes of motion intrinsically accessible to this enzyme. Here, we present the results from normal mode analysis using an elastic network model representation, which shows that the conformational mechanisms for substrate binding by NAGK strongly correlate with the intrinsic dynamics of the enzyme in the unbound form. We further analyzed the potential mechanisms of allosteric signalling within NAGK using a Markov model for network communication. Comparative analysis of the dynamics of family members strongly suggests that the low-frequency modes of motion and the associated intramolecular couplings that establish signal transduction are highly conserved among family members, in support of the paradigm sequence→structure→dynamics→function © 2010 Marcos et al

Quasi-continuous Interpolation Scheme for Pathways between Distant Configurations

A quasi-continuous interpolation (QCI) scheme is introduced for characterizing physically realistic initial pathways from which to initiate transition state searches and construct kinetic transition networks. Applications are presented for peptides, proteins, and a morphological transformation in an atomic cluster. The first step in each case involves end point alignment, and we describe the use of a shortest augmenting path algorithm for optimizing permutational isomers. The QCI procedure then employs an interpolating potential, which preserves the covalent bonding framework for the biomolecules and includes repulsive terms between unconstrained atoms. This potential is used to identify an interpolating path by minimizing contributions from a connected set of images, including terms corresponding to minima in the interatomic distances between them. This procedure detects unphysical geometries in the line segments between images. The most difficult cases, where linear interpolation would involve chain crossings, are treated by growing the structure an atom at a time using the interpolating potential. To test the QCI procedure, we carry through a series of benchmark calculations where the initial interpolation is coupled to explicit transition state searches to produce complete pathways between specified local minima.This work was supported by the Engineering and Physical Sciences Research Council [grant number EP/H042660/1]This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in the Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review. To access the final edited and published work see http://dx.doi.org/10.1021/ct300483

Automating the search of molecular motor templates by evolutionary methods

The first author is supported by a FPU grant (AP2007-03704) from the Ministerio de Educación of the Spanish Government, and has been supported by the BioEmergences project (code 28892) of the Sixth Framework Programme of the European Union. Our research group has been partially supported by the local government (Junta de Andalucía) through a grant for the GENEX project (P09-TIC-5123).Biological molecular motors are nanoscale devices capable of transforming chemical energy into mechanical work, which are being researched in many scientific disciplines. From a computational point of view, the characteristics and dynamics of these motors are studied at multiple time scales, ranging from very detailed and complex molecular dynamics simulations spanning a few microseconds, to extremely simple and coarse-grained theoretical models of their working cycles. However, this research is performed only in the (relatively few) instances known from molecular biology. In this work, results from elastic network analysis and behaviour-finding methods are applied to explore a subset of the configuration space of template molecular structures that are able to transform chemical energy into directed movement, for a fixed instance of working cycle. While using methods based on elastic networks limits the scope of our results, it enables the implementation of computationally lightweight methods, in a way that evolutionary search techniques can be applied to discover novel molecular motor templates. The results show that molecular motion can be attained from a variety of structural configurations, when a functional working cycle is provided. Additionally, these methods enable a new computational way to test hypotheses about molecular motors

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

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