RecA protein is the prototypical recombinase. Members of recombinase family can accurately repair double strand breaks in DNA. They also provide crucial links between pairs sister chromatids eukaryotic meiosis. A very broad outline how these proteins align homologous sequences and promote DNA exchange has long been known, as are crystal structures RecA-DNA pre- postsynaptic complexes; however, little known about homology searching conformations details bacterial genomes rapidly searched...

The phosphorylation of the microtubule-associated tau protein plays a key role in regulation its physiological function. In particular, hyperphosphorylation affects binding on tubulin surface, destabilizing tau-microtubule interface and leading to accumulation fibrillar aggregates brain. this work, we performed classical Molecular Dynamics simulations for tau-R2/tubulin assembly with various phosphorylations states serines 285, 289 293. We analyze resulting trajectories obtain detailed view...

This study investigates the effect of multiple phosphorylations Intrinsically Disordered Protein (IDP) tau on its hydrodynamic radius (Rh). Hyperphosphorylated is notably implicated in Alzheimer's disease The kinases responsible for adding phosphate groups are highly involved regulation biological processes such as cell division, signalling, and apoptosis and, particularly, development disease, especially those recognized by AT8 antibody. main objective this work to understand how...

Abstract Although reliable docking can now be achieved for systems that do not undergo important induced conformational change upon association, the presence of flexible surface loops, which must adapt to steric and electrostatic properties a partner, generally presents major obstacle. We report here first method allows large loop movements during systematic exploration possible arrangements two partners in terms position rotation. Our strategy consists taking into account an ensemble...

Abstract The oligomerization of amyloid beta (Aβ) peptides into soluble non-fibrillar species plays a critical role in the pathogenesis Alzheimer’s disease. However, it has been challenging to characterize tertiary and quaternary structures Aβ due their disordered nature high aggregation propensity. In this work, replica exchange molecular dynamics simulations were used explore conformational space 42 monomer. Among most populated transient states, we identified particular conformation which...

RecA family proteins are responsible for homology search and strand exchange. In bacteria, begins after binds an initiating single-stranded DNA (ssDNA) in the primary DNA-binding site, forming presynaptic filament. Once filament is formed, it interrogates double-stranded (dsDNA). During interrogation, bases dsDNA attempt to form Watson–Crick bonds with corresponding strand. Mismatch dependent instability base pairing heteroduplex exchange product could provide stringent recognition; however,...

Abstract Coarse grain modelling of macromolecules is a new approach, potentially well adapted to answer numerous issues, ranging from physics biology. We propose here an original DNA coarse model specifically dedicated protein‐DNA docking, crucial, but still largely unresolved, question in molecular Using representative set complexes, we first show that our able predict the interaction surface between macromolecular partners taken their bound form. In second part, impact sequence and...

Abstract Background Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms slow process generally involving routine tasks that should be found in robust library and not programmed from scratch for every software application. Results We present an object-oriented Python/C++ to help the development methods. This contains low-level routines like PDB-format manipulation functions as well high-level tools analyzing results. also illustrate ease use this with...

Homologous recombination is a fundamental process enabling the repair of double-strand breaks with high degree fidelity. In prokaryotes, it carried out by RecA nucleofilaments formed on single-stranded DNA (ssDNA). These filaments incorporate genomic sequences that are homologous to ssDNA and exchange strands. Due highly dynamic character this its rapid propagation along filament, sequence recognition strand mechanism remains unknown at structural level. The recently published structure...

Tau is an intrinsically disordered (IDP) microtubule-associated protein (MAP) that plays a key part in microtubule assembly and organization. The function of tau can be regulated by multiple phosphorylation sites. These post-translational modifications are known to decrease the binding affinity for microtubules, abnormal patterns involved Alzheimer's disease. Using all-atom molecular dynamics simulations, we compared conformational landscapes explored R2 repeat domain (which comprises strong...

We previously reported that a 24 amino acid peptide (NFL-TBS.40-63) corresponding to the tubulin-binding site located on light neurofilament subunit, selectively enters in glioblastoma cells where it disrupts their microtubule network and inhibits proliferation. Here, we analyzed structure-function relationships using an alanine-scanning strategy, order identify residues essential for these biological activities. showed majority of modified peptides present decreased or total loss penetrate...

During DNA recombination and repair, RecA family proteins must promote rapid joining of homologous DNA. Repeated sequences with >100 base pair lengths occupy more than 1% bacterial genomes; however, commitment to strand exchange was believed occur after testing ∼20–30 bp. If that were true, pairings between different copies long repeated would usually become irreversible. Our experiments reveal in the presence ATP hydrolysis even 75 bp sequence-matched products remain quite reversible....

Oligomeric macromolecules in the cell self-organize into a wide variety of geometrical motifs such as helices, rings or linear filaments. The recombinase proteins involved homologous recombination present many assembly motifs. Here, we examine particular polymorphic characteristics RecA, most studied member family, using an integrative approach that relates local modes monomer/monomer association to global architecture their screw-type organization. In our approach, are sampled via docking...

Homologous recombination is a fundamental process in all living organisms that allows the faithful repair of DNA double strand breaks, through exchange strands between homologous regions genome. Results three decades investigation and recent fruitful observations have unveiled key elements reaction mechanism, which proceeds along nucleofilaments recombinase proteins RecA family. Yet, one essential aspect has largely been overlooked when deciphering mechanism: while ATP hydrolyzed large...

In the present study, we searched for possible effects of DNA strandedness (single and double), on two types damages, frank strand breaks (FSB, observed at neutral pH) alkali labile sites (ALS, leading to alkaline induced by irradiation with γ-rays (60Co) or fast neutrons (p34,Be). Sequencing gel electrophoresis allowed us follow occurrence these damages each nucleotide site in single (ss-ss), double (ds-ds), half single-half (ss-ds ds-ss) stranded oligonucleotides. Globally, random...

We address a major obstacle to macromolecular docking algorithms by presenting new method that takes into account the induced conformational adjustment of flexible loops situated at protein/macromolecule interface. The method, MC2, is based on multiple copy representation loops, coupled with Monte Carlo search relative position macromolecules and their side chain conformations. selection optimal loop conformations place during cycling iterative weight each copy. describe here...

The microtubule-associated protein (MAP) tau plays a key role in the regulation of microtubule assembly and spatial organization. Tau hyperphosphorylation affects its binding on tubulin surface has been shown to be involved several pathologies such as Alzheimer's disease. As site lays close disordered highly flexible C-terminal tails (CTTs), these are likely impact tau-tubulin interaction. Since CTTs missing from available experimental structures, we used homology modeling build two complete...