Atomistic adsorption of PETase onto large-scale PET 3D-models that mimic reality.

Polyethylene terephthalate (PET) has been widely used in plastic products, leading to massive PET waste accumulation in ecosystems worldwide. Efforts to find greener processes for dealing with post-consumer PET waste led to the discovery of PET-degrading enzymes such as PETase (PETase). studies have provided valuable contributions to this field, shedding light on the catalytic mechanisms and substrate interactions in many PET hydrolase enzymes.

Histological features of immune cell infiltrate in lesional skin correlate with therapeutic response to dupilumab.

Over the past decade, dupilumab, a monoclonal human antibody that inhibits interleukin (IL)-4 and IL-13 signalling, has revolutionized the therapeutic management of moderate-to-severe atopic dermatitis (AD), facilitating long-term control of its signs and symptoms. The aim of this study was to identify histological predictors of the efficacy of dupilumab after 16 weeks of treatment in a cohort of 40 adults with moderate-to-severe AD who had undergone a skin biopsy for diagnostic purposes before treatment initiation. We found that Eczema Area and Severity Index (EASI) 75 and EASI 90 responses at week 16 were significantly associated with perivascular localization [odds ratio (OR) 17.

MiMiC: A high-performance framework for multiscale molecular dynamics simulations.

MiMiC is a framework for performing multiscale simulations in which loosely coupled external programs describe individual subsystems at different resolutions and levels of theory. To make it highly efficient and flexible, we adopt an interoperable approach based on a multiple-program multiple-data (MPMD) paradigm, serving as an intermediary responsible for fast data exchange and interactions between the subsystems. The main goal of MiMiC is to avoid interfering with the underlying parallelization of the external programs, including the operability on hybrid architectures (e.

Multiscale biomolecular simulations in the exascale era.

The complexity of biological systems and processes, spanning molecular to macroscopic scales, necessitates the use of multiscale simulations to get a comprehensive understanding. Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations are crucial for capturing processes beyond the reach of classical MD simulations. The advent of exascale computing offers unprecedented opportunities for scientific exploration, not least within life sciences, where simulations are essential to unravel intricate molecular mechanisms underlying biological processes.

Low grade of satisfaction related to the use of current systemic therapies among pustular psoriasis patients: a therapeutic unmet need to be fulfilled.

Introduction: Pustular psoriasis is considered a separate entity from plaque psoriasis and can be categorized as generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau, or palmoplantar pustulosis (PPP). Current guidelines mostly include treatment options that have not been specifically developed for the treatment of pustular psoriasis. The majority of them does not have indication for the treatment of pustular psoriasis.

Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors: A Retrospective, Multinational, Multicentre Study.

Background: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed.

Clinical Features and Response to Treatment in Elderly Subjects Affected by Hidradenitis Suppurativa: A Cohort Study.

Hidradenitis suppurativa (HS) is a chronic-relapsing inflammatory skin disease. It usually appears in the second and third decades, but a smaller proportion of patients develop late-onset HS. Geriatric HS, defined as the persistence or the development of HS after the age of 65 years, has been poorly explored.

Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail.

We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug's action.

Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations.

The initial phases of drug discovery - drug design - could benefit from first principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines - so far an unmet and crucial goal - will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance.

MiMiCPy: An Efficient Toolkit for MiMiC-Based QM/MM Simulations.

MiMiC is a highly flexible, extremely scalable multiscale modeling framework. It couples the CPMD (quantum mechanics, QM) and GROMACS (molecular mechanics, MM) codes. The code requires preparing separate input files for the two programs with a selection of the QM region.

Proton Transfers to DNA in Native Electrospray Ionization Mass Spectrometry: A Quantum Mechanics/Molecular Mechanics Study.

Native electrospray ionization-ion mobility mass spectrometry (N-ESI/IM-MS) is a powerful approach for low-resolution structural studies of DNAs in the free state and in complex with ligands. Solvent vaporization is coupled with proton transfers from ammonium ions to the DNA, resulting in a reduction of the DNA charge. Here we provide insight into these processes by classical molecular dynamics and quantum mechanics/molecular mechanics free energy calculations on the d(GpCpGpApApGpC) heptamer, for which a wealth of experiments is available.

Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes.

Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It has been co-administered with zinc against SARS-CoV-2 and soon dismissed because of safety issues. The structural features of Zn-CQ complexes and the effect of CQ on zinc distribution in cells are poorly known.

Wavefunction-Based Electrostatic-Embedding QM/MM Using CFOUR through MiMiC.

We present an interface of the wavefunction-based quantum chemical software CFOUR to the multiscale modeling framework MiMiC. Electrostatic embedding of the quantum mechanical (QM) part is achieved by analytic evaluation of one-electron integrals in CFOUR, while the rest of the QM/molecular mechanical (MM) operations are treated according to the previous MiMiC-based QM/MM implementation. Long-range electrostatic interactions are treated by a multipole expansion of the potential from the QM electron density to reduce the computational cost without loss of accuracy.

Mechanisms Underlying Proton Release in CLC-type F/H Antiporters.

The CLC family of anion channels and transporters includes Cl/H exchangers (blocked by F) and F/H exchangers (or CLCs). CLCs contain a glutamate (E318) in the central anion-binding site that is absent in CLC Cl/H exchangers. The X-ray structure of the protein from (CLC-eca) shows that E318 tightly binds to F when the gating glutamate (E118; highly conserved in the CLC family) faces the extracellular medium.

Machine Learning of Allosteric Effects: The Analysis of Ligand-Induced Dynamics to Predict Functional Effects in TRAP1.

Allosteric molecules provide a powerful means to modulate protein function. However, the effect of such ligands on distal orthosteric sites cannot be easily described by classical docking methods. Here, we applied machine learning (ML) approaches to expose the links between local dynamic patterns and different degrees of allosteric inhibition of the ATPase function in the molecular chaperone TRAP1.

Molecular Basis of CLC Antiporter Inhibition by Fluoride.

CLC channels and transporters conduct or transport various kinds of anions, with the exception of fluoride, which acts as an effective inhibitor. Here, we performed sub-nanosecond DFT-based QM/MM simulations of the anion/proton exchanger ClC-ec1 and observed that fluoride binds incoming protons within the selectivity filter, with excess protons shared with the gating glutamate E148. Depending on E148 conformation, the competition for the proton can involve either a direct F/E148 interaction or the modulation of water molecules bridging the two anions.

All-Atom Simulations Disclose How Cytochrome Reductase Reshapes the Substrate Access/Egress Routes of Its Partner CYP450s.

Cytochromes P450 enzymes (CYP450s) promote the oxidative metabolism of a variety of substrates via the electrons supplied by the cytochrome P450 reductase (CPR) and upon formation of a CPR/CYP450 adduct. In spite of the pivotal regulatory importance of this process, the impact of CPR binding on the functional properties of its partner CYP450 remains elusive. By performing multiple microsecond-long all-atom molecular dynamics simulations of a 520 000-atom model of a CPR/CYP450 adduct embedded in a membrane mimic, we disclose the molecular terms for their interactions, considering the aromatase (HA) enzyme as a proxy of the CYP450 family.

Extreme Scalability of DFT-Based QM/MM MD Simulations Using MiMiC.

We present a highly scalable DFT-based QM/MM implementation developed within MiMiC, a recently introduced multiscale modeling framework that uses a loose-coupling strategy in conjunction with a multiple-program multiple-data (MPMD) approach. The computation of electrostatic QM/MM interactions is parallelized exploiting both distributed- and shared-memory strategies. Here, we use the efficient CPMD and GROMACS programs as QM and MM engines, respectively.