Although therapeutically targeting a single signaling pathway that drives tumor development and/or progression has been effective for number of cancers, in many cases this approach not successful. Targeting networks pathways, instead isolated may overcome problem, which is probably due to the extreme heterogeneity human tumors. However, possibility such be spatially arranged specialized subcellular compartments often considered pathway-oriented drug discovery and influence design new agents....

Pompe disease (PD) is a metabolic myopathy due to the deficiency of lysosomal enzyme α-glucosidase (GAA). The only approved treatment for this disorder, replacement with recombinant human GAA (rhGAA), has shown limited therapeutic efficacy in some PD patients. Pharmacological chaperone therapy (PCT), either alone or combination replacement, been proposed as an alternative strategy. However, chaperones identified so far also are active site-directed molecules and potential inhibitors target...

The self-organization of peptides into amyloidogenic oligomers is one the key events for a wide range molecular and degenerative diseases. Atomic-resolution characterization mechanisms responsible aggregation process resulting structures thus necessary step to improve our understanding determinants these pathologies. To address this issue, we combine accelerated sampling properties replica exchange dynamics simulations based on OPEP coarse-grained potential with atomic resolution description...

Molecular self- and co-assembly allow the formation of diverse well-defined supramolecular structures with notable physical properties. Among associating molecules, amino acids are especially attractive due to their inherent biocompatibility simplicity. The biologically active enantiomer l-histidine (l-His) plays structural functional roles in proteins but does not self-assemble form discrete nanostructures. In order expand space include l-His-containing materials, we explored l-His all...

Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at crossroads multiple signaling pathways associated with cell proliferation and viability. Here we present combined structure- dynamics-based computational design strategy, taking flexibility receptor lead peptidic antagonist into account explicitely, identify nonpeptidic small molecule 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) as structurally novel inhibitor...

Background: Heat shock protein 90 (Hsp90) is a molecular chaperone that involved in signaling pathways for cell proliferation, survival, and cellular adaptation. Inhibitors of Hsp90 are being examined as cancer therapeutic agents, but the mechanism their anticancer activity still unclear. We investigated target acute myeloid leukemia (AML) by use inhibitor shepherdin (a novel peptidyl antagonist interaction between survivin, which regulator proliferation viability cancer). Methods: studied...

Molecular switching and ligand-based modulation of the 90-kDa heat-shock protein (Hsp90) chaperone activity may ultimately facilitate conformational coupling to ATPase cycle along with activation recruitment broad range client proteins. We present an atomic resolution analysis Hsp90 N-terminal domain (NTD) binding energy landscape by simulating dynamics a partners. show that molecular be linked (i) local folding-unfolding transitions "active site lid" upon (ii) differences in underlying as...

L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently in clinics are characterized by high vivo instability, short half-life requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they sensitive proteases (cathepsin B asparagine endopeptidase) that over-expressed...

SARS-CoV-2 is a health threat with dire socioeconomical consequences. As the crucial mediator of infection, viral glycosylated spike protein (S) has attracted most attention and at center efforts to develop therapeutics diagnostics. Herein, we use an original decomposition approach identify energetically uncoupled substructures as antibody binding sites on fully S. Crucially, all that required are unbiased MD simulations; no prior knowledge properties or ad hoc parameter combinations needed....

Background The conversion of the cellular prion protein (PrPC) into infectious form (PrPSc) is key event in induced neurodegenerations. This process believed to involve a multi-step conformational transition from an α-helical β-sheet-rich state. In addition difference, PrPSc exhibits as covalent signature sulfoxidation M213. To investigate whether such modification may play role misfolding we have studied impact methionine oxidation on dynamics and energetics HuPrP(125–229) α-fold....

Background Mutations in the cellular prion protein associated to familial disorders severely increase likelihood of its misfolding into pathogenic conformers. Despite their postulation as incompatible elements with native fold, these mutations rarely modify state structure. However they variably have impact on thermodynamic stability and metabolism PrPC properties PrPSc aggregates. To investigate whether affect dynamic HuPrP(125-229) α-fold find possible common patterns effects that could...

Abstract Partially modified retro‐ (PMR) and retro‐inverso (PMRI) ψ[NHCH(CF 3 )]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity variable length by aza‐Michael reaction enantiomerically pure α‐amino esters peptides with geometrically N ‐4,4,4‐trifluorocrotonoyl‐oxazolidin‐2‐ones. The factors underlying the observed moderate to good diastereocontrol investigated. conformations model PMR‐ψ[NHCH(CF tripeptides studied solution 1 H NMR...

A broader exploitation of enzymes in organic synthesis can be achieved by increasing their tolerance toward solvents. In this study, the stability and activity Baeyer-Villiger monooxygenases from Thermobifida fusca (PAMO) Acinetobacter sp. (CHMO) presence water miscible solvents were compared. PAMO was more stable than CHMO. The concentration solvent (v/v) at which it halved its (C(50) ) 4- to 16-fold higher that observed for For PAMO, C(50) varied 16% 55% followed destabilizing order...

Although intensively studied, the high-resolution crystal structure of peptide DFNKF, core-segment human calcitonin, has never been described. Here we report how use iodination as a strategy to promote crystallisation and facilitate phase determination, allowed us solve, for first time, single-crystal X-ray DFNKF derivative. Computational studies suggest that both iodinated wild-type peptides populate very similar conformations. Furthermore, conformer found in solid-state is one most...

Biocompatible graft copolymers from bacterial poly(γ-glutamic acid) and poly(lactic are realized using a “grafting to” approach combined with click chemistry.

Herein, we present a novel Hamiltonian replica exchange protocol for classical molecular dynamics simulations of protein folding/unfolding. The scheme starts from the analysis energy-networks responsible stabilization folded conformation, by means energy-decomposition approach. In this framework, compact energetic map native state is generated preliminary short (MD) simulation in explicit solvent. This simplified an eigenvalue decomposition. highest components eigenvector associated with...

Human serum albumin (HSA) is involved physiologically in heme scavenging; turn, heme-albumin (HSA-heme-Fe) displays globin-like properties. Here, the allosteric effect of ibuprofen and warfarin on local atomic structure around ferric heme-Fe (heme-Fe(III)) atom HSA-heme-Fe (HSA-heme-Fe(III)) has been probed by Fe-K edge X-ray absorption spectroscopy (XAS). The quantitative analysis extended fine (EXAFS) signals modeling near (XANES) spectral features demonstrated that binding modify...

PARP-1 inhibition has been studied over the last decades for treatment of various diseases. Despite fact that several molecules act as inhibitors, a reduced number compounds are used in clinical practice. To identify new with discriminatory inhibitory function, explicit-solvent molecular dynamics simulations using different inhibitors bound to catalytic domain were performed. The representative structures obtained generate structure-based pharmacophores, taking into account dynamic features...

Herein we investigate the molecular bases of DNA polymerase I conformational dynamics that underlie replication fidelity enzyme. Such is determined by changes promote rejection incorrect nucleotides before chemical ligation step. We report a comprehensive atomic resolution study wild type and mutant enzymes in different bound states starting from crystal structures, using extensive (MD) simulations cover total timespan ~ 5 microseconds. The resulting trajectories are examined via combination...