A multi-resolution model to capture both global fluctuations of an enzyme and molecular recognition in the ligand-binding site

In multi-resolution simulations, different system components are simultaneously modelled at different levels of resolution, these being smoothly coupled together. In the case of enzyme systems, computationally expensive atomistic detail is needed in the active site to capture the chemistry of substrate binding. Global properties of the rest of the protein also play an essential role, determining the structure and fluctuations of the binding site; however, these can be modelled on a coarser level. Similarly, in the most computationally efficient scheme only the solvent hydrating the active site requires atomistic detail. We present a methodology to couple atomistic and coarse-grained protein models, while solvating the atomistic part of the protein in atomistic water. This allows a free choice of which protein and solvent degrees of freedom to include atomistically, without loss of accuracy in the atomistic description. This multi-resolution methodology can successfully model stable ligand binding, and we further confirm its validity via an exploration of system properties relevant to enzymatic function. In addition to a computational speedup, such an approach can allow the identification of the essential degrees of freedom playing a role in a given process, potentially yielding new insights into biomolecular function

Advantages and challenges in coupling an ideal gas to atomistic models in adaptive resolution simulations

In adaptive resolution simulations, molecular fluids are modeled employing different levels of resolution in different subregions of the system. When traveling from one region to the other, particles change their resolution on the fly. One of the main advantages of such approaches is the computational efficiency gained in the coarse-grained region. In this respect the best coarse-grained system to employ in the low resolution region would be the ideal gas, making intermolecular force calculations in the coarse-grained subdomain redundant. In this case, however, a smooth coupling is challenging due to the high energetic imbalance between typical liquids and a system of non-interacting particles. In the present work, we investigate this approach, using as a test case the most biologically relevant fluid, water. We demonstrate that a successful coupling of water to the ideal gas can be achieved with current adaptive resolution methods, and discuss the issues that remain to be addressed

ALADYN: a web server for aligning proteins by matching their large-scale motion

The ALADYN web server aligns pairs of protein structures by comparing their internal dynamics and detecting regions that sustain similar large-scale movements. The latter often accompany functional conformational changes in proteins and enzymes. The ALADYN dynamics-based alignment can therefore highlight functionally-oriented correspondences that could be more elusive to sequence- or structure-based comparisons. The ALADYN server takes the structure files of the two proteins as input. The optimal relative positioning of the molecules is found by maximizing the similarity of the pattern of structural fluctuations which are calculated via an elastic network model. The resulting alignment is presented via an interactive graphical Java applet and is accompanied by a number of quantitative indicators and downloadable data files. The ALADYN web server is freely accessible at the http://aladyn.escience-lab.org address

Corresponding Functional Dynamics across the Hsp90 Chaperone Family: Insights from a Multiscale Analysis of MD Simulations

Understanding how local protein modifications, such as binding small-molecule ligands, can trigger and regulate large-scale motions of large protein domains is a major open issue in molecular biology. We address various aspects of this problem by analyzing and comparing atomistic simulations of Hsp90 family representatives for which crystal structures of the full length protein are available: mammalian Grp94, yeast Hsp90 and E.coli HtpG. These chaperones are studied in complex with the natural ligands ATP, ADP and in the Apo state. Common key aspects of their functional dynamics are elucidated with a novel multi-scale comparison of their internal dynamics. Starting from the atomic resolution investigation of internal fluctuations and geometric strain patterns, a novel analysis of domain dynamics is developed. The results reveal that the ligand-dependent structural modulations mostly consist of relative rigid-like movements of a limited number of quasi-rigid domains, shared by the three proteins. Two common primary hinges for such movements are identified. The first hinge, whose functional role has been demonstrated by several experimental approaches, is located at the boundary between the N-terminal and Middle-domains. The second hinge is located at the end of a three-helix bundle in the Middle-domain and unfolds/unpacks going from the ATP- to the ADP-state. This latter site could represent a promising novel druggable allosteric site common to all chaperones

Effectiveness and safety of bimekizumab for the treatment of plaque psoriasis. a real-life multicenter study—IL PSO (Italian landscape psoriasis)

Introduction: Bimekizumab is a monoclonal antibody that targets Interleukin-17 A and F, approved for the treatment of moderate-to-severe plaque psoriasis. While bimekizumab has been evaluated in several phase-III clinical trials, real-world evidence is still very limited. Method: This multicenter retrospective study included patients affected by plaque psoriasis treated with bimekizumab from May 1, 2022 to April 30, 2023, at 19 Italian referral hospitals. Patients affected by moderate-to-severe plaque psoriasis eligible for systemic treatments were included. The effectiveness of bimekizumab was evaluated in terms of reduction in psoriasis area and severity index (PASI) compared with baseline at weeks 4 and 16. The main outcomes were the percentages of patients achieving an improvement of at least 75% (PASI75), 90% (PASI90) and 100% (PASI100) in PASI score. Results: The study included 237 patients who received at least one injection of bimekizumab. One hundred and seventy-one patients and 114 reached four and 16 weeks of follow-up, respectively. Complete skin clearance was achieved by 43.3% and 75.4% of patients at weeks 4 and 16, respectively. At week 16, 86.8% of patients reported no impact on their quality of life. At week 16, there were no significant differences between bio-naïve and bio-experienced patients in terms of PASI75, PASI90 and PASI100. The most commonly reported adverse events (AEs) were oral candidiasis (10.1%). No severe AEs or AEs leading to discontinuation were observed throughout the study. Conclusion: Our experience supports the effectiveness and tolerability of bimekizumab in a real-world setting with similar results compared with phase-III clinical trials

Owning the problem: Media portrayals of overweight dogs and the shared determinants of the health of human and companion animal populations

Weight-related health problems have become a common topic in Western mass media. News-coverage has also extended to overweight pets, particularly since 2003 when the U.S. National Academy of Sciences announced that obesity was also afflicting co-habiting companion animals in record numbers. To characterize and track views in popular circulation on causes, consequences and responsibilities vis-à-vis weight gain and obesity, in pets as well as in people, this study examines portrayals of overweight dogs that appeared from 2000 through 2009 in British, American and Australian mass media. The ethnographic content analysis drew inspiration from the literature in population health, animal-human relationships, communication framing and the active nature of texts in cosmopolitan societies. Three main types of media articles about overweight dogs appeared during this period: 1) reports emphasizing facts and figures; 2) stories emphasizing personal prescriptions for dog owners, and 3) societal critiques. To help ordinary people make sense of canine obesity, media articles often highlight that dogs share the lifestyle of their human companion or owner, yet the implications of shared social and physical environments is rarely considered when it comes to solutions. Instead, media coverage exhorts people who share their lives with overweight dogs to ‘own the problem’ and, with resolve, to normalize their dog’s physical condition by imposing dietary, exercise and relationship changes, thereby individualizing culpability rather than linking it to broader systemic issues. Keywords: Companion animals; Media; Narrative analysis; Obesity; Public understandin

Knotted vs. Unknotted Proteins: Evidence of Knot-Promoting Loops

Knotted proteins, because of their ability to fold reversibly in the same topologically entangled conformation, are the object of an increasing number of experimental and theoretical studies. The aim of the present investigation is to assess, on the basis of presently available structural data, the extent to which knotted proteins are isolated instances in sequence or structure space, and to use comparative schemes to understand whether specific protein segments can be associated to the occurrence of a knot in the native state. A significant sequence homology is found among a sizeable group of knotted and unknotted proteins. In this family, knotted members occupy a primary sub-branch of the phylogenetic tree and differ from unknotted ones only by additional loop segments. These "knot-promoting" loops, whose virtual bridging eliminates the knot, are found in various types of knotted proteins. Valuable insight into how knots form, or are encoded, in proteins could be obtained by targeting these regions in future computational studies or excision experiments

The Italian Consensus Conference on FAI Syndrome in Athletes (Cotignola Agreement)

Background. Femoro-acetabular impingement (FAI) is an important topic in literature because of its strong relationship with sport populations. Methods. Sixty-five experts participated in "this Consensus Conference (CC)". They discussed, voted and approved a consensus document on the FAI syndrome in athletes. Results. The CC experts approved document provided suggestions concerning: 1) Epidemiology of FAI; 2) Clinical evaluation; 3) Radiological evaluation; 4) Conserva-tive treatment; 5) Surgical criteria; 6) Surgical techniques; 7) Post-surgical rehabilita-tion; 8) Outcome evaluation; 9) FAI-associated clinical frameworks. Conclusions. The CC offers a multidisciplinary approach to the diagnosis and treat-ment of FAI syndrome in athletes taking into account all the different steps needed to approach this pathology in sport populations