Time filter

Source Type

Chakroun N.,King's College London | Fornili A.,King's College London | Prigent S.,French National Institute for Agricultural Research | Kleinjung J.,UK National Institute for Medical Research | And 4 more authors.
Journal of Chemical Theory and Computation | Year: 2013

Prion diseases are fatal neurodegenerative diseases characterized by the formation of β-rich oligomers and the accumulation of amyloid fibrillar deposits in the central nervous system. Understanding the conversion of the cellular prion protein into its β-rich polymeric conformers is fundamental to tackling the early stages of the development of prion diseases. In this paper, we have identified unfolding and refolding steps critical to the conversion into a β-rich conformer for different constructs of the ovine prion protein by molecular dynamics simulations. By combining our results with in vitro experiments, we show that the folded C-terminus of the ovine prion protein is able to recurrently undergo a drastic conformational change by displacement of the H1 helix, uncovering of the H2H3 domain, and formation of persistent β-sheets between H2 and H3 residues. The observed β-sheets refold toward the C-terminus exposing what we call a "bending region" comprising residues 204-214. This is strikingly coincident with the region harboring mutations determining the fate of the prion oligomerization process. The β-rich intermediate is used here for the construction of a putative model for the assembly into an oligomeric aggregate. The results presented here confirm the importance of the H2H3 domain for prion oligomer formation and therefore its potential use as molecular target in the design of novel prion inhibitors. © 2013 American Chemical Society.


Pandini A.,King's College London | Fornili A.,King's College London | Fraternali F.,King's College London | Fraternali F.,Thomas Young Center for Theory and Simulation of Materials | Kleinjung J.,UK National Institute for Medical Research
Bioinformatics | Year: 2013

Motivation: GSATools is a free software package to analyze conformational ensembles and to detect functional motions in proteins by means of a structural alphabet. The software integrates with the widely used GROMACS simulation package and can generate a range of graphical outputs. Three applications can be supported: (i) investigation of the conformational variability of local structures; (ii) detection of allosteric communication; and (iii) identification of local regions that are critical for global functional motions. These analyses provide insights into the dynamics of proteins and allow for targeted design of functional mutants in theoretical and experimental studies. Availability: The C source code of the GSATools, along with a set of pre-compiled binaries, is freely available under GNU General Public License from http://mathbio.nimr.mrc.ac.uk/wiki/GSATools. Contact: alessandro.pandini@kcl. ac.uk or jkleinj@nimr.mrc.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. © 2013 The Author 2013. Published by Oxford University Press.


Pandini A.,UK National Institute for Medical Research | Pandini A.,King's College London | Fornili A.,King's College London | Fraternali F.,King's College London | And 2 more authors.
FASEB Journal | Year: 2012

Allostery offers a highly specific way to modulate protein function. Therefore, understanding this mechanism is of increasing interest for protein science and drug discovery. However, allosteric signal transmission is difficult to detect experimentally and to model because it is often mediated by local structural changes propagating along multiple pathways. To address this, we developed a method to identify communication pathways by an information- theoretical analysis of molecular dynamics simulations. Signal propagation was described as information exchange through a network of correlated local motions, modeled as transitions between canonical states of protein fragments. The method was used to describe allostery in two-component regulatory systems. In particular, the transmission from the allosteric site to the signaling surface of the receiver domain NtrC was shown to be mediated by a layer of hub residues. The location of hubs preferentially connected to the allosteric site was found in close agreement with key residues experimentally identified as involved in the signal transmission. The comparison with the networks of the homologues CheY and FixJ highlighted similarities in their dynamics. In particular, we showed that a preorganized network of fragment connections between the allosteric and functional sites exists already in the inactive state of all three proteins. © The Author(s).


Fornili A.,King's College London | Pandini A.,King's College London | Pandini A.,UK National Institute for Medical Research | Lu H.-C.,King's College London | And 2 more authors.
Journal of Chemical Theory and Computation | Year: 2013

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society.

Loading Thomas Young Center for Theory and Simulation of Materials collaborators
Loading Thomas Young Center for Theory and Simulation of Materials collaborators