A protein–DNA docking benchmark

We present a protein–DNA docking benchmark containing 47 unbound–unbound test cases of which 13 are classified as easy, 22 as intermediate and 12 as difficult cases. The latter shows considerable structural rearrangement upon complex formation. DNA-specific modifications such as flipped out bases and base modifications are included. The benchmark covers all major groups of DNA-binding proteins according to the classification of Luscombe et al., except for the zipper-type group. The variety in test cases make this non-redundant benchmark a useful tool for comparison and development of protein–DNA docking methods. The benchmark is freely available as download from the internet

SAMPLEX: Automatic mapping of perturbed and unperturbed regions of proteins and complexes

<p>Abstract</p> <p>Background</p> <p>The activity of proteins within the cell is characterized by their motions, flexibility, interactions or even the particularly intriguing case of partially unfolded states. In the last two cases, a part of the protein is affected either by binding or unfolding and the detection of the respective perturbed and unperturbed region(s) is a fundamental part of the structural characterization of these states. This can be achieved by comparing experimental data of the same protein in two different states (bound/unbound, folded/unfolded). For instance, measurements of chemical shift perturbations (CSPs) from NMR ¹H-¹⁵N HSQC experiments gives an excellent opportunity to discriminate both moieties.</p> <p>Results</p> <p>We describe an innovative, automatic and unbiased method to distinguish perturbed and unperturbed regions in a protein existing in two distinct states (folded/partially unfolded, bound/unbound). The SAMPLEX program takes as input a set of data and the corresponding three-dimensional structure and returns the confidence for each residue to be in a perturbed or unperturbed state. Its performance is demonstrated for different applications including the prediction of disordered regions in partially unfolded proteins and of interacting regions in protein complexes.</p> <p>Conclusions</p> <p>The proposed approach is suitable for partially unfolded states of proteins, local perturbations due to small ligands and protein-protein interfaces. The method is not restricted to NMR data, but is generic and can be applied to a wide variety of information.</p

WeNMR : the tale of virtual research community in NMR and structural biology

Structural biology and life sciences in general, and NMR in particular, have always been associated with advanced computing. The current challenges in the post-genomic era call for virtual research platforms that provide the worldwide research community with both user-friendly tools, platforms for data analysis and exchange, and an underlying e-Infrastructure. WeNMR, a three-year European Commission co-funded project started in November 2010, groups different research teams into a worldwide virtual research community. It builds on the established eNMR e-Infrastructure and its steadily growing virtual organisation, which is currently the second largest VO in the area of life sciences. WeNMR provides an e-Infrastructure platform and Science Gateway for structural biology. It involves researchers from around the world and will build bridges to other areas of structural biology

DeepRank-GNN-esm: A graph neural network for scoring protein-protein models using protein language model

Motivation: Protein-Protein interactions (PPIs) play critical roles in numerous cellular processes. By modelling the 3D structures of the correspond protein complexes valuable insights can be obtained, providing, e.g. starting points for drug and protein design. One challenge in the modelling process is however the identification of near-native models from the large pool of generated models. To this end we have previously developed DeepRank-GNN, a graph neural network that integrates structural and sequence information to enable effective pattern learning at PPI interfaces. Its main features are related to the Position Specific Scoring Matrices (PSSMs), which are computationally expensive to generate, significantly limits the algorithm's usability. Results: We introduce here DeepRank-GNN-esm that includes as additional features protein language model embeddings from the ESM-2 model. We show that the ESM-2 embeddings can actually replace the PSSM features at no cost in-, or even better performance on two PPI-related tasks: scoring docking poses and detecting crystal artifacts. This new DeepRank version bypasses thus the need of generating PSSM, greatly improving the usability of the software and opening new application opportunities for systems for which PSSM profiles cannot be obtained or are irrelevant (e.g. antibody-antigen complexes)

Dynamic control of selectivity in the ubiquitination pathway revealed by an ASP to GLU substitution in an intra-molecular salt-bridge network

Ubiquitination relies on a subtle balance between selectivity and promiscuity achieved through specific interactions between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Here, we report how a single aspartic to glutamic acid substitution acts as a dynamic switch to tip the selectivity balance of human E2s for interaction toward E3 RING-finger domains. By combining molecular dynamic simulations, experimental yeast-two-hybrid screen of E2-E3 (RING) interactions and mutagenesis, we reveal how the dynamics of an internal salt-bridge network at the rim of the E2-E3 interaction surface controls the balance between an “open”, binding competent, and a “closed”, binding incompetent state. The molecular dynamic simulations shed light on the fine mechanism of this molecular switch and allowed us to identify its components, namely an aspartate/glutamate pair, a lysine acting as the central switch and a remote aspartate. Perturbations of single residues in this network, both inside and outside the interaction surface, are sufficient to switch the global E2 interaction selectivity as demonstrated experimentally. Taken together, our results indicate a new mechanism to control E2-E3 interaction selectivity at an atomic level, highlighting how minimal changes in amino acid side-chain affecting the dynamics of intramolecular salt-bridges can be crucial for protein-protein interactions. These findings indicate that the widely accepted sequence-structure-function paradigm should be extended to sequence-structure-dynamics-function relationship and open new possibilities for control and fine-tuning of protein interaction selectivity

Характеристика механизма функционирования форм хозяйствования с иностранными инвестициями

Механизм функционирования предприятия с иностранными инвестициями неразрывно связан с понятиями "хозяйственный механизм" и "механизм функционирования предприятия". В экономической науке советского периода широко применялся термин "хозяйственный механизм". Рассматривался хозяйственный механизм отдельного предприятия, отрасли, экономики страны в целом, то есть рассматривался хозяйственный механизм экономических систем различного уровня

Вимоги СОТ для державного регулювання регіонального ринку сільськогосподарської продукції України

Державне регулювання України, як країни з перехідною ринковою економікою, повинно базуватися на основних положеннях та вимогах СОТ (Світової організації торгівлі). Україна вибрала курс Європейської інтеграції, тому її економіка повинна відповідати та працювати по принципах світового ринку. Мета досліджень: проаналізувати основні положення та вимоги Світової організації торгівлі, основні моменти державного регулювання ринку сільськогосподарської продукції, що відповідають принципам світового ринку і які повинні працювати в умовах України

Medical Students' Skills and Needs for Training in Breaking Bad News

This study assessed medical students' perception of individual vs. group training in breaking bad news (BBN) and explored training needs in BBN. Master-level students (N = 124) were randomised to group training (GT)—where only one or two students per group conducted a simulated patient (SP) interview, which was discussed collectively with the faculty—or individual training (IT)—where each student conducted an SP interview, which was discussed during individual supervision. Training evaluation was based on questionnaires, and the videotaped interviews were rated using the Roter Interaction Analysis System. Students were globally satisfied with the training. Still, there were noticeable differences between students performing an interview (GT/IT) and students observing interviews (GT). The analysis of the interviews showed significant differences according to scenarios and to gender. Active involvement through SP interviews seems required for students to feel able to reach training objectives. The evaluation of communication skills, revealing a baseline heterogeneity, supports individualised trainin