Annalisa Bordogna - Academia.edu (original) (raw)

Papers by Annalisa Bordogna

Journal of Chemical Information and Modeling, Nov 2, 2011

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-ARNT-Sim (P... more The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-ARNT-Sim (PAS) containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As no experimentally determined structures of the AhR ligand binding domain (LBD) are available and previous homology models were only derived from apo template structures, we developed a new model based on holo X-ray structures of the hypoxia-inducible factor 2α (HIF-2α) PAS B domain, targeted to improve the accuracy of the binding site for molecular docking applications. We experimentally confirmed the ability of two HIF-2α crystallographic ligands to bind to the mAhR with relatively high affinity and demonstrated that they are AhR agonists, thus justifying the use of the holo HIF-2α structures as templates. A specific modeling/ docking approach was proposed to predict the binding modes of AhR ligands in the modeled LBD. It was validated by comparison of the calculated and the experimental binding affinities of active THS ligands and TCDD for the mAhR and by functional activity analysis using several mAhR mutants generated on the basis of the modeling results. Finally the ability of the proposed approach to reproduce the different affinities of TCDD for AhRs of different species was confirmed, and a first test of its reliability in virtual screening is carried out by analyzing the correlation between the calculated and experimental binding affinities of a set of 14 PCDDs.

In microelectronic device manufacturing, photosensitive organic insulators (POIs) are widely used... more In microelectronic device manufacturing, photosensitive organic insulators (POIs) are widely used during passivation steps to protect and preserve the chips from damage due to subsequent processes and from the external environment. To ensure high performance and to maintain chip quality, a well-controlled POI lithography process and corresponding defectivity monitoring are needed. In this work, we present an automated method developed by STMicroelectronics and KLA for POI defectivity and process control employing a KLA 8 Series inspection system with illumination in the visible range. The highly sensitive macro inspection tool with dedicated analysis approaches and solutions successfully enabled the detection of the principal defects of interest, the identification of defectivity root causes through automatic classification and review, and the evaluation of the layer thickness and uniformity through reflected intensity heatmaps. For several months, this protocol has been applied to the production environment, proving to be effective in detecting even small deviations from the standard process. Here, we present some promising results obtained with this strategy, highlighting the benefits in terms of rework reduction and improved equipment management.

Journal of Computational Chemistry, Nov 17, 2010

Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by... more Ligand-protein docking is increasingly used in Drug Discovery. The initial limitations imposed by a reduced availability of target protein structures have been overcome by the use of theoretical models, especially those derived by homology modeling techniques. While this greatly extended the use of docking simulations, it also introduced the need for general and robust criteria to estimate the reliability of docking results given the model quality. To this end, a large-scale experiment was performed on a diverse set including experimental structures and homology models for a group of representative ligand-protein complexes. A wide spectrum of model quality was sampled using templates at different evolutionary distances and different strategies for targettemplate alignment and modeling. The obtained models were scored by a selection of the most used model quality indices. The binding geometries were generated using AutoDock, one of the most common docking programs. An important result of this study is that indeed quantitative and robust correlations exist between the accuracy of docking results and the model quality, especially in the binding site. Moreover, state-of-the-art indices for model quality assessment are already an effective tool for an a priori prediction of the accuracy of docking experiments in the context of groups of proteins with conserved structural characteristics.

Protein Engineering Design & Selection, Jun 1, 2007

Aim of this work is to assess the informativeness of protein dynamics in the detection of similar... more Aim of this work is to assess the informativeness of protein dynamics in the detection of similarities among distant homologous proteins. To this end, an approach to perform large-scale comparisons of protein domain flexibilities is proposed. CONCOORD is confirmed as a reliable method for fast conformational sampling. The root mean square fluctuation of alpha carbon positions in the essential dynamics subspace is employed as a measure of local flexibility and a synthetic index of similarity is presented. The dynamics of a large collection of protein domains from ASTRAL/SCOP40 is analyzed and the possibility to identify relationships, at both the family and the superfamily levels, on the basis of the dynamical features is discussed. The obtained picture is in agreement with the SCOP classification, and furthermore suggests the presence of a distinguishable familiar trend in the flexibility profiles. The results support the complementarity of the dynamical and the structural information, suggesting that information from dynamics analysis can arise from functional similarities, often partially hidden by a static comparison. On the basis of this first test, flexibility annotation can be expected to help in automatically detecting functional similarities otherwise unrecoverable.

Proteins: Structure, Function, and Bioinformatics, 2010

The recent CAPRI rounds have introduced new docking challenges in the form of protein-RNA complex... more The recent CAPRI rounds have introduced new docking challenges in the form of protein-RNA complexes, multiple alternative interfaces, and an unprecedented number of targets for which homology modeling was required. We present here the performance of HADDOCK and its web server in the CAPRI experiment and discuss the strengths and weaknesses of data-driven docking. HADDOCK was successful for 6 out of 9 complexes (6 out of 11 targets) and accurately predicted the individual interfaces for two more complexes. The HADDOCK server, which is the first allowing the simultaneous docking of generic multi-body complexes, was successful in 4 out of 7 complexes for which it participated. In the scoring experiment, we predicted the highest number of targets of any group. The main weakness of data-driven docking revealed from these last CAPRI results is its vulnerability for incorrect experimental data related to the interface or the stoichiometry of the complex. At the same time, the use of experimental and/or predicted information is also the strength of our approach as evidenced for those targets for which accurate experimental information was available (e.g., the 10 three-stars predictions for T40!). Even when the models show a wrong orientation, the individual interfaces are generally well predicted with an average coverage of 60% ± 26% over all targets. This makes data-driven docking particularly valuable in a biological context to guide experimental studies like, for example, targeted mutagenesis.

Protein Engineering, Design and Selection, 2007

Journal of Computational Chemistry, 2010

Journal of Chemical Information and Modeling, 2011

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helixÀloopÀhelix Per-ARNT-Sim (P... more The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helixÀloopÀhelix Per-ARNT-Sim (PAS) containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD). As no experimentally determined structures of the AhR ligand binding domain (LBD) are available and previous homology models were only derived from apo template structures, we developed a new model based on holo X-ray structures of the hypoxia-inducible factor 2α (HIF-2α) PAS B domain, targeted to improve the accuracy of the binding site for molecular docking applications. We experimentally confirmed the ability of two HIF-2α crystallographic ligands to bind to the mAhR with relatively high affinity and demonstrated that they are AhR agonists, thus justifying the use of the holo HIF-2α structures as templates. A specific modeling/docking approach was proposed to predict the binding modes of AhR ligands in the modeled LBD. It was validated by comparison of the calculated and the experimental binding affinities of active THS ligands and TCDD for the mAhR and by functional activity analysis using several mAhR mutants generated on the basis of the modeling results. Finally the ability of the proposed approach to reproduce the different affinities of TCDD for AhRs of different species was confirmed, and a first test of its reliability in virtual screening is carried out by analyzing the correlation between the calculated and experimental binding affinities of a set of 14 PCDDs.

Proteins-Structure Function and Bioinformatics, 2013

Information-driven docking is currently one of the most successful approaches to obtain structura... more Information-driven docking is currently one of the most successful approaches to obtain structural models of protein interactions as demonstrated in the latest round of CAPRI. While various experimental and computational techniques can be used to retrieve information about the binding mode, the availability of three-dimensional structures of the interacting partners remains a limiting factor. Fortunately, the wealth of structural information gathered by large-scale initiatives allows for homology-based modeling of a significant fraction of the protein universe. Defining the limits of information-driven docking based on such homology models is therefore highly relevant. Here we show, using previous CAPRI targets, that out of a variety of measures, the global sequence identity between template and target is a simple but reliable predictor of the achievable quality of the docking models. This indicates that a well-defined overall fold is critical for the interaction. Furthermore, the quality of the data at our disposal to characterize the interaction plays a determinant role in the success of the docking. Given reliable interface information we can obtain acceptable predictions even at low global sequence identity. These results, which define the boundaries between trustworthy and unreliable predictions, should guide both experts and nonexperts in defining the limits of what is achievable by docking. This is highly relevant considering that the fraction of the interactome amenable for docking is only bound to grow as the number of experimentally solved structures increases.

Appropriate solutions for post-lithographic defect management and process tool control are fundam... more Appropriate solutions for post-lithographic defect management and process tool control are fundamental to ensure better chip quality and yield maintenance through the reduction of wafers at risk. The increasing demand in terms of wafer production capacity and sensitivity requirements from the automotive, MEMS and Internet of Things markets is leading advanced legacy semiconductor fabs to challenge their conventional after-develop-inspection (ADI) paradigm. In this work, we present a high throughput photolithography step monitoring scheme, developed by STMicroelectronics and KLA, employing an 8 Series patterned wafer defect inspection system for wafer frontside inspection and review. Namely, we demonstrate the capacity to capture die level defects together with full wafer excursions with a significant level of sensitivity, as well as a beneficial impact on yield improvement and lithography cell control. Moreover, we propose fast and reliable methods for monitoring the pattern shift a...