Using molecular dynamics simulations in an explicit aqueous solvent, we examine the binding of fluoride versus iodide to a spherical macromolecule with both hydrophobic and positively charged patches. Rationalizing our observations, we divide the ion association interaction into two mechanisms: (1) poorly solvated iodide ions are attracted to hydrophobic surface patches, while (2) the strongly solvated fluoride and to a minor extent also iodide bind via cation-anion interactions. Quantitatively, the binding affinities vary significantly with the accessibility of the charged groups as well as the surface potential; therefore, we expect the ion-macromolecule association to be modulated by the local surface characteristics of the (bio-)macromolecule. The observed cation-anion pairing preference is in excellent agreement with experimental data.

• MeSH
• fluoridy MeSH
• hydrofobní a hydrofilní interakce * MeSH
• ionty chemie   MeSH
• jodidy MeSH
• makromolekulární látky chemie   MeSH
• počítačová simulace MeSH
• rozpouštědla MeSH
• statická elektřina MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluoridy MeSH
• ionty MeSH
• jodidy MeSH
• makromolekulární látky MeSH
• rozpouštědla MeSH
• voda MeSH

Silymarin is a well-known standardized extract from the seeds of milk thistle (Silybum marianum L., Asteraceae) with a pleiotropic effect on human health, including skin anticancer potential. Detailed characterization of flavonolignans properties affecting interactions with human skin was of interest. The partition coefficients log Pow of main constitutive flavonolignans, taxifolin and their respective dehydro derivatives were determined by a High Performance Liquid Chromatography (HPLC) method and by mathematical (in silico) approaches in n-octanol/water and model lipid membranes. These parameters were compared with human skin intake ex vivo. The experimental log Pow values for individual diastereomers were estimated for the first time. The replacement of n-octanol with model lipid membranes in the theoretical lipophilicity estimation improved the prediction strength. During transdermal transport, all the studied compounds permeated the human skin ex vivo; none of them reached the acceptor liquid. Both experimental/theoretical tools allowed the studied polyphenols to be divided into two groups: low (taxifolin, silychristin, silydianin) vs. high (silybin, dehydrosilybin, isosilybin) lipophilicity and skin intake. In silico predictions can be usefully applied for estimating general lipophilicity trends, such as skin penetration or accumulation predictions. However, the theoretical models cannot yet provide the dermal delivery differences of compounds with very similar physico-chemical properties; e.g., between diastereomers.

• Klíčová slova
• Silybum marianum, experimental and computational hydrophobicity, flavonoids, flavonolignans, skin intake, theoretical lipid membrane models,
• MeSH
• hydrofobní a hydrofilní interakce MeSH
• lékové transportní systémy * MeSH
• lidé MeSH
• ostropestřec mariánský chemie   MeSH
• permeabilita MeSH
• polyfenoly aplikace a dávkování   chemie   farmakologie   MeSH
• škára účinky léků   MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• polyfenoly MeSH

Charybdotoxin, belonging to the group of so-called scorpion toxins, is a short peptide able to block many voltage-gated potassium channels, such as mKv1.3, with high affinity. We use a reliable homology model based on the high-resolution crystal structure of the 94% sequence identical homologue Kv1.2 for charybdotoxin docking followed by molecular dynamics simulations to investigate the mechanism and energetics of unbinding, tracing the behavior of the channel protein and charybdotoxin during umbrella-sampling simulations as charybdotoxin is moved away from the binding site. The potential of mean force is constructed from the umbrella sampling simulations and combined with K(d) and free energy values gained experimentally using the patch-clamp technique to study the free energy of binding at different ion concentrations and the mechanism of the charybdotoxin-mKv1.3 binding process. A possible charybdotoxin binding mechanism is deduced that includes an initial hydrophobic contact followed by stepwise electrostatic interactions and finally optimization of hydrogen bonds and salt bridges.

• MeSH
• charybdotoxin chemie   metabolismus   MeSH
• draslíkový kanál Kv1.3 chemie   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• metoda terčíkového zámku MeSH
• molekulární sekvence - údaje MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• simulace molekulární dynamiky MeSH
• statická elektřina MeSH
• terciární struktura proteinů MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• charybdotoxin MeSH
• draslíkový kanál Kv1.3 MeSH

Hydrophobicity can either be determined experimentally or predicted by means of commercially available programs. In the studies concerning biological activities of pyrazine analogues of chalcones, 3-(2-hydroxyphenyl)-1-(pyrazin-2-yl)prop-2-en-1-ones were more potent than the corresponding 3-(4-hydroxyphenyl)-1-(pyrazin-2-yl)prop-2-en-1-ones. As the difference in lipophilicity may be a factor responsible for the difference in the potency, R(M) values of the compounds were determined by RP-TLC and compared with logP values calculated by various commercially available programs. Important discrepancies were found between experimental and computational lipophilicity data. Therefore, we have tried to find a reliable method for calculating R(M) values from in silico derived molecular parameters. The R(M) values obtained with the chromatographic system consisting of Silufol UV 254 plates impregnated with silicon oil as the stationary phase and acetone-citrate buffer (pH=3) 50:50 (v/v) as the mobile phase correlated well with van der Waals volumes (V(W)) and hydration energies [Formula: see text] derived of molecular models calculated on RHF/AM1 level.

• MeSH
• flavonoidy chemie   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• organická chemie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• flavonoidy MeSH

A combined experimental-computational approach was used to study the self-organization and microenvironment of 1-methylnaphthalene (1MN) deposited on the surface of artificial snow grains from vapors at 238 K. The specific surface area of this snow (1.1 × 10(4) cm(2) g(-1)), produced by spraying very fine droplets of pure water from a nebulizer into liquid nitrogen, was determined using valerophenone photochemistry to estimate the surface coverage by 1MN. Fluorescence spectroscopy at 77 K, in combination with molecular dynamics simulations, and density functional theory (DFT) and second-order coupled cluster (CC2) calculations, provided evidence for the occurrence of ground- and excited-state complexes (excimers) and other associates of 1MN on the snow grains' surface. Only weak excimer fluorescence was observed for a loading of 5 × 10(-6) mol kg(-1), which is ∼2-3 orders of magnitude below monolayer coverage. However, the results indicate that the formation of excimers is favored at higher surface loadings (>5 × 10(-5) mol kg(-1)), albeit still being below monolayer coverage. The calculations of excited states of monomer and associated moieties suggested that a parallel-displaced arrangement is responsible for the excimer emission observed experimentally, although some other associations, such as T-shape dimer structures, which do not provide excimer emission, can still be relatively abundant at this surface concentration. The hydrophobic 1MN molecules, deposited on the ice surface, which is covered by a relatively flexible quasi-liquid layer at 238 K, are then assumed to be capable of dynamic motion resulting in the formation of energetically preferred associations to some extent. The environmental implications of organic compounds' deposition on snow grains and ice are discussed.

• MeSH
• kvantová teorie * MeSH
• naftaleny chemie   MeSH
• povrchové vlastnosti MeSH
• simulace molekulární dynamiky * MeSH
• sníh chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-methylnaphthalene MeSH Prohlížeč
• naftaleny MeSH

The actin cytoskeleton is a dynamic structure that coordinates numerous fundamental processes in eukaryotic cells. Dozens of actin-binding proteins are known to be involved in the regulation of actin filament organization or turnover and many of these are stimulus-response regulators of phospholipid signaling. One of these proteins is the heterodimeric actin-capping protein (CP) which binds the barbed end of actin filaments with high affinity and inhibits both addition and loss of actin monomers at this end. The ability of CP to bind filaments is regulated by signaling phospholipids, which inhibit the activity of CP; however, the exact mechanism of this regulation and the residues on CP responsible for lipid interactions is not fully resolved. Here, we focus on the interaction of CP with two signaling phospholipids, phosphatidic acid (PA) and phosphatidylinositol (4,5)-bisphosphate (PIP(2)). Using different methods of computational biology such as homology modeling, molecular docking and coarse-grained molecular dynamics, we uncovered specific modes of high affinity interaction between membranes containing PA/phosphatidylcholine (PC) and plant CP, as well as between PIP(2)/PC and animal CP. In particular, we identified differences in the binding of membrane lipids by animal and plant CP, explaining previously published experimental results. Furthermore, we pinpoint the critical importance of the C-terminal part of plant CPα subunit for CP-membrane interactions. We prepared a GST-fusion protein for the C-terminal domain of plant α subunit and verified this hypothesis with lipid-binding assays in vitro.

• MeSH
• aktin zastřešující proteiny antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• fosfatidylinositolfosfáty chemie   metabolismus   MeSH
• fylogeneze MeSH
• hydrofobní a hydrofilní interakce MeSH
• kur domácí MeSH
• kyseliny fosfatidové chemie   metabolismus   MeSH
• molekulární modely MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• proteiny huseníčku antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• ptačí proteiny antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• vazba proteinů MeSH
• výpočetní biologie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• aktin zastřešující proteiny MeSH
• fosfatidylinositolfosfáty MeSH
• kyseliny fosfatidové MeSH
• proteiny huseníčku MeSH
• ptačí proteiny MeSH

Mutations of cysteine are often introduced to e.g. avoid formation of non-physiological inter-molecular disulfide bridges in in-vitro experiments, or to maintain specificity in labeling experiments. Alanine or serine is typically preferred, which usually do not alter the overall protein stability, when the original cysteine was surface exposed. However, selecting the optimal mutation for cysteines in the hydrophobic core of the protein is more challenging. In this work, the stability of selected Cys mutants of 14-3-3ζ was predicted by free-energy calculations and the obtained data were compared with experimentally determined stabilities. Both the computational predictions as well as the experimental validation point at a significant destabilization of mutants C94A and C94S. This destabilization could be attributed to the formation of hydrophobic cavities and a polar solvation of a hydrophilic side chain. A L12E, M78K double mutant was further studied in terms of its reduced dimerization propensity. In contrast to naïve expectations, this double mutant did not lead to the formation of strong salt bridges, which was rationalized in terms of a preferred solvation of the ionic species. Again, experiments agreed with the calculations by confirming the monomerization of the double mutants. Overall, the simulation data is in good agreement with experiments and offers additional insight into the stability and dimerization of this important family of regulatory proteins.

• Klíčová slova
• 14-3-3 protein, Differential scanning calorimetry, Free energy calculation, Molecular dynamics simulation, Protein stability, Thermodynamic integration,
• MeSH
• cystein chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• kinetika MeSH
• konformace proteinů MeSH
• lidé MeSH
• molekulární modely MeSH
• multimerizace proteinu * MeSH
• mutace MeSH
• počítačová simulace MeSH
• proteiny 14-3-3 chemie   genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• termodynamika * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystein MeSH
• proteiny 14-3-3 MeSH
• YWHAZ protein, human MeSH Prohlížeč

Organic-inorganic (O-I) nanomaterials are versatile platforms for an incredible high number of applications, ranging from heterogeneous catalysis to molecular sensing, cell targeting, imaging, and cancer diagnosis and therapy, just to name a few. Much of their potential stems from the unique control of organic environments around inorganic sites within a single O-I nanomaterial, which allows for new properties that were inaccessible using purely organic or inorganic materials. Structural and mechanistic characterization plays a key role in understanding and rationally designing such hybrid nanoconstructs. Here, we introduce a general methodology to identify and classify local (supra)molecular environments in an archetypal class of O-I nanomaterials, i.e., self-assembled monolayer-protected gold nanoparticles (SAM-AuNPs). By using an atomistic machine-learning guided workflow based on the Smooth Overlap of Atomic Positions (SOAP) descriptor, we analyze a collection of chemically different SAM-AuNPs and detect and compare local environments in a way that is agnostic and automated, i.e., with no need of a priori information and minimal user intervention. In addition, the computational results coupled with experimental electron spin resonance measurements prove that is possible to have more than one local environment inside SAMs, being the thickness of the organic shell and solvation primary factors in the determining number and nature of multiple coexisting environments. These indications are extended to complex mixed hydrophilic-hydrophobic SAMs. This work demonstrates that it is possible to spot and compare local molecular environments in SAM-AuNPs exploiting atomistic machine-learning approaches, establishes ground rules to control them, and holds the potential for the rational design of O-I nanomaterials instructed from data.

• Klíčová slova
• ESR, SOAP, fluorinated nanoparticles, machine learning, mixed monolayers, multiscale modeling, nanoconfinement,
• MeSH
• hydrofobní a hydrofilní interakce MeSH
• kovové nanočástice * chemie   MeSH
• nanostruktury * chemie   MeSH
• zlato chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• zlato MeSH

Interaction of polycations with lipid membranes is a very important issue in many biological and medical applications such as gene delivery or antibacterial usage. In this work, we address the influence of hydrophobic substitution of strong polycations containing quaternary ammonium groups on the polymer-zwitterionic membrane interactions. In particular, we focus on the polymer tendency to adsorb on or/and incorporate into the membrane. We used complementary experimental and computational methods to enhance our understanding of the mechanism of the polycation-membrane interactions. Polycation adsorption on liposomes was assessed using dynamic light scattering (DLS) and zeta potential measurements. The ability of the polymers to form hydrophilic pores in the membrane was evaluated using a calcein-release method. The polymer-membrane interaction at the molecular scale was explored by performing atomistic molecular dynamics (MD) simulations. Our results show that the length of the alkyl side groups plays an essential role in the polycation adhesion on the zwitterionic surface, while the degree of substitution affects the polycation ability to incorporate into the membrane. Both the experimental and computational results show that the membrane permeability can be dramatically affected by the amount of alkyl side groups attached to the polycation main chain.

• MeSH
• adsorpce MeSH
• amoniové sloučeniny chemie   MeSH
• dynamický rozptyl světla MeSH
• elektronová kryomikroskopie MeSH
• hydrofobní a hydrofilní interakce MeSH
• liposomy chemie   metabolismus   MeSH
• polyaminy chemie   metabolismus   MeSH
• polyelektrolyty MeSH
• simulace molekulární dynamiky MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amoniové sloučeniny MeSH
• liposomy MeSH
• polyaminy MeSH
• polycations MeSH Prohlížeč
• polyelektrolyty MeSH

OBJECTIVES: The herbal drug aristolochic acid (AA) derived from Aristolochia species has been shown to be the cause of aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and their urothelial malignancies. One of the common features of AAN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumor development. One cause for these different responses may be individual differences in the activities of the enzymes catalyzing the biotransformation of AA. Thus, the identification of enzymes principally involved in the metabolism of AAI, the major toxic component of AA, and detailed knowledge of their catalytic specificities is of major importance. Human cytochrome P450 (CYP) 1A1 and 1A2 enzymes were found to be responsible for the AAI reductive activation to form AAI-DNA adducts, while its structurally related analogue, CYP1B1 is almost without such activity. However, knowledge of the differences in mechanistic details of CYP1A1-, 1A2-, and 1B1- mediated reduction is still lacking. Therefore, this feature is the aim of the present study. METHODS: Molecular modeling capable of evaluating interactions of AAI with the active site of human CYP1A1, 1A2 and 1B1 under the reductive conditions was used. In silico docking, employing soft-soft (flexible) docking procedure was used to study the interactions of AAI with the active sites of these human enzymes. RESULTS: The predicted binding free energies and distances between an AAI ligand and a heme cofactor are similar for all CYPs evaluated. AAI also binds to the active sites of CYP1A1, 1A2 and 1B1 in similar orientations. The carboxylic group of AAI is in the binding position situated directly above heme iron. This ligand orientation is in CYP1A1/1A2 further stabilized by two hydrogen bonds; one between an oxygen atom of the AAI nitro-group and the hydroxyl group of Ser122/Thr124; and the second bond between an oxygen atom of dioxolane ring of AAI and the hydroxyl group of Thr497/Thr498. For the CYP1B1:AAI complex, however, any hydrogen bonding of the nitro-group of AAI is prevented as Ser122/Thr124 residues are in CYP1B1 protein replaced by hydrophobic residue Ala133. CONCLUSION: The experimental observations indicate that CYP1B1 is more than 10× less efficient in reductive activation of AAI than CYP1A2. The docking simulation however predicts the binding pose and binding energy of AAI in the CYP1B1 pocket to be analogous to that found in CYP1A1/2. We believe that the hydroxyl group of S122/T124 residue, with its polar hydrogen placed close to the nitro group of the substrate (AAI), is mechanistically important, for example it could provide a proton required for the stepwise reduction process. The absence of a suitable proton donor in the AAI-CYP1B1 binary complex could be the key difference, as the nitro group is in this complex surrounded only by the hydrophobic residues with potential hydrogen donors not closer than 5 Å.

• MeSH
• adukty DNA chemie   metabolismus   MeSH
• Aristolochia chemie   MeSH
• aromatické hydroxylasy chemie   genetika   metabolismus   MeSH
• chemické modely MeSH
• cytochrom P-450 CYP1A1 chemie   genetika   metabolismus   MeSH
• cytochrom P-450 CYP1A2 chemie   genetika   metabolismus   MeSH
• cytochrom P450 CYP1B1 MeSH
• hydrofobní a hydrofilní interakce účinky léků   MeSH
• katalytická doména účinky léků   MeSH
• kyseliny aristolochové škodlivé účinky   chemie   farmakokinetika   MeSH
• léky rostlinné čínské škodlivé účinky   chemie   farmakokinetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• nemoci ledvin chemicky indukované   MeSH
• nitroreduktasy škodlivé účinky   chemie   farmakokinetika   MeSH
• počítačová simulace MeSH
• sekvence aminokyselin MeSH
• terciární struktura proteinů účinky léků   MeSH
• vodíková vazba účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA MeSH
• aristolochic acid I MeSH Prohlížeč
• aromatické hydroxylasy MeSH
• CYP1A1 protein, human MeSH Prohlížeč
• CYP1A2 protein, human MeSH Prohlížeč
• CYP1B1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P450 CYP1B1 MeSH
• kyseliny aristolochové MeSH
• léky rostlinné čínské MeSH
• nitroreduktasy MeSH