1,720,976 research outputs found
A Metadynamics approach for the study of osmolytes: unraveling glycine betaine protecting effect
No full textModelling protein-protein interactions
No full textProtein-protein interactions are fundamental to many biological processes, from signal transduction to cytoskeleton assembly and are therefore important targets for pharmaceutical research1. Particular attention is given here to the network of interactions occurring between tubulin dimers, in order to understand the nature of their association to form microtubules (MTs), polymeric cellular structures involved in mitosis. Given their primary importance in cell division, microtubules are interesting targets for antimitotic agents to be used in cancer therapies2. Currently, most of the MTs targeted drugs in use derive from screenings of natural compounds or their modifications. Following a different approach, we present here an in silico design of novel peptides able to interfere with MTs dynamic, thus acting as inhibitors of cancer cells proliferation. A molecular dynamics (MD) simulation was carried out on a system composed of two tubulin dimers in explicit water solvent, followed by interdimer binding energy evaluations and computational alanine scanning3 of the interface residues. It resulted that the binding energy is not evenly distributed over the protein-protein interface, but is concerntrated on some crucial amino acids, determinant for subunits association, defined as “hot-spots”. A subsequent simulation of a tubulin tetramer in complex with a vinblastine molecule in its active site pointed out how this antimitotic agent strongly reduces the number of interactions, thus explaining its microtubule destabilizing properties. Protein subsequences including a number of hot-spots were then used as a starting point for the development of peptides that could target different sites on tubulin with respect to vinblastine and other traditional chemoteherapeutic agents. The so designed peptides underwent further MD simulations in complex with tubulin, in order to evaluate if they conserved binding ability even when no longer inserted in the protein structure. The most promising ones were then sinthesized and underwent biological tests proving their ability to effectively alter MTs morphology and stability
Solvent effect on halogen bonding : the case of the I···O interaction
No full textThe solvent effect on the I⋯O halogen bonding in complexes of iodobenzene derivatives with formaldehyde has been investigated by systematically varying the substituents on the iodobenzene ring. Calculations have been performed at MP2 and DFT levels of theory, using the aug-cc-pVDZ basis set and the pseudopotential for iodine. Within the DFT approach, a series of the most widely used exchange-correlation functionals have been considered, comprising PBE, PBE0, B3LYP, BH&HLYP, M06-2X and M06-HF. Results obtained in diethylether and in water using the conductor-like polarizable continuum model (CPCM) have been compared with in vacuo results. Though halogen bonding distances were found to systematically shorten when moving from vacuo to diethylether and then to water, the associated interaction energies showed a decrease in absolute value, indicating that solvent has a destabilizing effect on this interaction. By comparison with MP2 results, all the considered functionals, B3LYP excepted, have been found adequate to describe halogen bonding. As far as the interaction energies are concerned, the best performance was obtained with the M06-HF functional in vacuo and the PBE functional in solution. The geometrical parameters characterizing halogen bonds were better reproduced by the M06-2X functional
Vinblastine perturbation of tubulin protofilament structure: a computational insight
No full textTubulin is a heterodimeric protein whose self assembly leads to the formation of protofilaments and of more complex structures called microtubules, key components of the cytoskeleton which have a fundamental role in the cell division process. Due to its biological function, tubulin is the target of many antitumoral molecules that exert their action on proliferating tumoral cells. Among these drugs, vinblastine has been widely used in therapy for a long time, albeit its mechanism of interaction with tubulin has remained elusive until recently. Vinblastine acts as a microtubule destabilizing agent and induces the formation of curved or ring-shaped tubulin polymers instead of linear protofilaments in vitro. In this paper we compare, using molecular dynamics simulations and free energy calculations, the network of interactions that allow the assembly of model linear protofilaments with those present in curved tubulin polymers complexed with vinblastine. It is shown that vinblastine, wedging between tubulin heterodimers, actually mediates part of the interactions between them and acts by crosslinking the two proteins, leading to the observed curved polymers rather than to their disassembly
Halogen Bonds with Benzene : an Assessment of DFT Functionals
No full textThe performance of an extensive set of density functional theory functionals has been tested against CCSD(T) and MP2 results, extrapolated to the complete basis set (CBS) limit, for the interaction of either DCl or DBr (D = H, HCC, F, and NC) with the aromatic system of benzene. It was found that double hybrid functionals explicitly including dispersion, that is, B2PLYPD and mPW2PLYPD, provide the better agreement with the CCSD(T)/CBS results on both energies and equilibrium geometry, indicating the importance of dispersive contributions in determining this interaction. Among the less expensive functionals, the better performance is provided by the ωB97X and M062X functionals, while the ωB97XD and B97D functionals are shown to work very well for bromine complexes but not so well for chlorine complexes
Halogen Bonding in ligand-receptor systems in the framework of classical force fields
No full textHalogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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