Structural dynamics of the TPR domain of the peroxisomal cargo receptor Pex5 in Trypanosoma.

Peroxisomal protein import has been identified as a valid target in trypanosomiases, an important health threat in Central and South America. The importomer is built of multiple peroxins (Pex) and structural characterization of these proteins facilitates rational inhibitor development. We report crystal structures of the Trypanosoma brucei and T.

Exploring the inhibitory potential of -designed small peptides on Hp0231 (DsbK), a periplasmic oxidoreductase involved in disulfide bond formation.

is a bacterium that colonizes the gastric epithelium, which affects millions of people worldwide. infection can lead to various gastrointestinal diseases, including gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Conventional antibiotic therapies face challenges due to increasing antibiotic resistance and patient non-compliance, necessitating the exploration of alternative treatment approaches.

Two-Stage Recognition Mechanism of the SARS-CoV-2 Receptor-Binding Domain to Angiotensin-Converting Enzyme-2 (ACE2).

The SARS-CoV-2 virus, commonly known as COVID-19, occurred in 2019. It is a highly contagious illness with effects ranging from mild symptoms to severe illness. It is also one of the best-known pathogens since more than 200,000 scientific papers occurred in the last few years.

Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment.

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target.

-Terminally Lipidated Sialorphin Analogs-Synthesis, Molecular Modeling, In Vitro Effect on Enkephalins Degradation by NEP and Treatment of Intestinal Inflammation in Mice.

Pharmacotherapy for inflammatory bowel disease (IBD) is difficult, and some patients do not respond to currently available treatments. Therefore, the discovery of novel anti-IBD agents is imperative. Our aim was the synthesis of lipidated analogs of sialorphin and the in vitro characterization of their effect on the degradation of Met-enkephalin by neutral endopeptidase (NEP).

A Novel Cryptic Clostridial Peptide That Kills Bacteria by a Cell Membrane Permeabilization Mechanism.

This work reports detailed characteristics of the antimicrobial peptide Intestinalin (P30), which is derived from the LysC enzyme of Clostridium intestinale strain URNW. The peptide shows a broader antibacterial spectrum than the parental enzyme, showing potent antimicrobial activity against clinical strains of Gram-positive staphylococci and Gram-negative pathogens and causing between 3.04 ± 0.

Low-Molecular Pyrazine-Based DNA Binders: Physicochemical and Antimicrobial Properties.

Pyrazine and its derivatives are a large group of compounds that exhibit broad biological activity, the changes of which can be easily detected by a substituent effect or a change in the functional group. The present studies combined theoretical research with the density functional theory (DFT) approach (B3LYP/6-311+G**) and experimental (potentiometric and spectrophotometric) analysis for a thorough understanding of the structure of chlorohydrazinopyrazine, its physicochemical and cytotoxic properties, and the site and nature of interaction with DNA. The obtained results indicated that 2-chloro-3-hydrazinopyrazine (2Cl3HP) displayed the highest affinity to DNA.

Peptidomimetics Based on -Terminus of Blm10 Stimulate Human 20S Proteasome Activity and Promote Degradation of Proteins.

Degradation of misfolded, redundant and oxidatively damaged proteins constitutes one of the cellular processes which are influenced by the 20S proteasome. However, its activity is generally thought to decrease with age which leads to the gradual accumulation of abnormal proteins in cells and their subsequent aggregation. Therefore, increasing proteasomal degradation constitutes a promising strategy to delay the onset of various age-related diseases, including neurodegenerative disorders.

Theoretical Investigation of the Coronavirus SARS-CoV-2 (COVID-19) Infection Mechanism and Selectivity.

The SARS-CoV-2 virus, commonly known as COVID-19, first occurred in December 2019 in Wuhan, Hubei Province, China. Since then, it has become a tremendous threat to human health. With a pandemic threat, it is in the significant interest of the scientific world to establish its method of infection.

Influence of Temperature and Salt Concentration on the Hydrophobic Interactions of Adamantane and Hexane.

One of the definitions of hydrophobic interactions is the aggregation of nonpolar particles in a polar solvent, such as water. While this phenomenon appears to be very simple, it is crucial for many complex processes, such as protein folding, to take place. In this work, the hydrophobic association of adamantane and hexane at various temperatures and ionic strengths was studied using molecular dynamics simulations with the AMBER 16.

Cathepsin C inhibition as a potential treatment strategy in cancer.

Epidemiological studies established an association between chronic inflammation and higher risk of cancer. Inhibition of proteolytic enzymes represents a potential treatment strategy for cancer and prevention of cancer metastasis. Cathepsin C (CatC) is a highly conserved lysosomal cysteine dipeptidyl aminopeptidase required for the activation of pro-inflammatory neutrophil serine proteases (NSPs, elastase, proteinase 3, cathepsin G and NSP-4).

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers).

Modeling protein structures with the coarse-grained UNRES force field in the CASP14 experiment.

The UNited RESidue (UNRES) force field was tested in the 14th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP14), in which larger oligomeric and multimeric targets were present compared to previous editions. Three prediction modes were tested (i) ab initio (the UNRES group), (ii) contact-assisted (the UNRES-contact group), and (iii) template-assisted (the UNRES-template group). For most of the targets, the contact restraints were derived from the server models top-ranked by the DeepQA method, while the DNCON2 method was used for 11 targets.

A Peptidomimetic Fluorescent Probe to Detect the Trypsin β2 Subunit of the Human 20S Proteasome.

This work describes the chemical synthesis, combinatorial selection, and enzymatic evaluation of peptidomimetic fluorescent substrates specific for the trypsin-like (β2) subunit of the 20S human proteasome. After deconvolution of a library comprising nearly 6000 compounds composed of peg substituted diaminopropionic acid DAPEG building blocks, the sequence ABZ-Dap(O2(Cbz))-Dap(GO1)-Dap(O2(Cbz))-Arg-ANB-NH, where ABZ is 2-aminobenzoic acid, and ANB- 5 amino 2- nitro benzoic acid was selected. Its cleavage followed sigmoidal kinetics, characteristic for allosteric enzymes, with = 3.

Scale-consistent approach to the derivation of coarse-grained force fields for simulating structure, dynamics, and thermodynamics of biopolymers.

In this chapter the scale-consistent approach to the derivation of coarse-grained force fields developed in our laboratory is presented, in which the effective energy function originates from the potential of mean force of the system under consideration and embeds atomistically detailed interactions in the resulting energy terms through use of Kubo's cluster-cumulant expansion, appropriate selection of the major degrees of freedom to be averaged out in the derivation of analytical approximations to the energy terms, and appropriate expression of the interaction energies at the all-atom level in these degrees of freedom. Our approach enables the developers to find correct functional forms of the effective coarse-grained energy terms, without having to import them from all-atom force fields or deriving them on a heuristic basis. In particular, the energy terms derived in such a way exhibit correct dependence on coarse-grained geometry, in particular on site orientation.

Improved Consensus-Fragment Selection in Template-Assisted Prediction of Protein Structures with the UNRES Force Field in CASP13.

The method for protein-structure prediction, which combines the physics-based coarse-grained UNRES force field with knowledge-based modeling, has been developed further and tested in the 13th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP13). The method implements restraints from the consensus fragments common to server models. In this work, the server models to derive fragments have been chosen on the basis of quality assessment; a fully automatic fragment-selection procedure has been introduced, and Dynamic Fragment Assembly pseudopotentials have been fully implemented.

Evaluation of the scale-consistent UNRES force field in template-free prediction of protein structures in the CASP13 experiment.

The recent NEWCT-9P version of the coarse-grained UNRES force field for proteins, with scale-consistent formulas for the local and correlation terms, has been tested in the CASP13 experiment of the blind-prediction of protein structure, in the ab initio, contact-assisted, and data-assisted modes. Significant improvement of the performance has been observed with respect to the CASP11 and CASP12 experiments (by over 10 GDT_TS units for the ab initio mode predictions and by over 15 GDT_TS units for the contact-assisted prediction, respectively), which is a result of introducing scale-consistent terms and improved handling of contact-distance restraints. As in previous CASP exercises, UNRES ranked higher in the free modeling category than in the general category that included template based modeling targets.

1-Substituted sialorphin analogues-synthesis, molecular modelling and in vitro effect on enkephalins degradation by NEP.

Rat sialorphin (Gln-His-Asn-Pro-Arg) is a natural blocker of neprilysin (NEP) that belongs to the family of endogenous opioid peptide-degrading enzymes. Studies have confirmed the efficiency of sialorphin in blocking the activity of NEP, both in vitro and in vivo. It has been demonstrated that this inhibitor has a strong analgesic, anti-inflammatory, immunological and metabolic effect either directly or indirectly by affecting the level of Met/Leu-enkephalins.

Introduction of Phosphorylated Residues into the UNRES Coarse-Grained Model: Toward Modeling of Signaling Processes.

Phosphorylated proteins take part in many signaling pathways and play a key role in homeostasis regulation. The all-atom force fields enable us to study the systems containing phosphorylated proteins, but they are limited to short time scales. In this paper, we report the extension of the physics-based coarse-grained UNRES force field to treat systems with phosphorylated amino-acid residues.

Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.

Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases.

A new protein nucleic-acid coarse-grained force field based on the UNRES and NARES-2P force fields.

Based on the coarse-grained UNRES and NARES-2P models of proteins and nucleic acids, respectively, developed in our laboratory, in this work we have developed a coarse-grained model of systems containing proteins and nucleic acids. The UNRES and NARES-2P effective energy functions have been applied to the protein and nucleic-acid components of a system, respectively, while protein-nucleic-acid interactions have been described by the respective coarse-grained potentials developed in our recent work (Yin et al., J.

An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12.

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP.

Use of the UNRES force field in template-assisted prediction of protein structures and the refinement of server models: Test with CASP12 targets.

Knowledge-based methods are, at present, the most effective ones for the prediction of protein structures; however, their results heavily depend on the similarity of a target sequence to those of proteins with known structures. On the other hand, the physics-based methods, although still less accurate and more expensive to execute, are independent of databases and give reasonable results where the knowledge-based methods fail because of weak sequence similarity. Therefore, a plausible approach seems to be the use of knowledge-based methods to determine the sections of the structures that correspond to sufficient sequence similarity and physics-based methods to determine the remaining structure.

Alanine scan of sialorphin and its hybrids with opiorphin: synthesis, molecular modelling and effect on enkephalins degradation.

Enkephalins are involved in a number of physiological processes. However, these peptides are quickly degraded by peptidases, e.g.