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Papers by Yevgeny Moskovitz

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Thermally induced shape memory poly(ε-caprolactone) (PCL)-based polymers are one of the most exte... more Thermally induced shape memory poly(ε-caprolactone) (PCL)-based polymers are one of the most extensively researched families of biocompatible materials. They are degradable under physiological conditions and have high applicability in general biomedical engineering, with cross-linked PCL networks being particularly useful for tissue engineering. In this study, we used the optimized potentials for liquid simulations (OPLS) force field, which is well suited for describing intermolecular interactions in biomolecules, and the class II polymer consistent force field (PCFF) to investigate the properties of telechelic PCL with diacrylates as reactive functionalities on its end groups. PCFF has been specifically parameterized for simulating synthetic polymeric materials. We compare the findings of all-atom molecular dynamics simulations with known experimental data and theoretical assumptions to verify the applicability of both these force fields. We estimated the melt density, volume, transition temperatures, and mechanical characteristics of two-branched PCL diacrylates with a molecular weight of 2481 Da. Our findings point to the utility of the aforementioned force fields in predicting the properties of PCL-based polymers. It also opens avenues for developing PCL cross-linked polymer models and employing OPLS to investigate the interactions of synthetic polymers with biomolecules. 34 monomers. This allows the activity of the protein to be 35 altered or tuned, while the protein remains anchored to 36 surfaces and sustains its extracellular enzymatic activity. 6 When 37 the active site is replicated in the imprinted polymer matrix, 38 protein function can be completely mimicked by the polymer 39 during the molecular imprinting process.

Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurologi... more Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying this phenomenon remain unclear. We performed 100 ns molecular dynamics (MD) simulations of the NMDAR structure embedded in a dioleoylphosphatidylcholine (DOPC) lipid bilayer solvated in water at 1 bar, hydrostatic 25 bar, and in helium at 25 bar. MD simulations showed that in contrast to hydrostatic pressure, high pressure helium causes substantial distortion of the DOPC membrane due to its accumulation between the two monolayers: reduction of the Sn-1 and Sn-2 DOPC chains and helium-dependent dehydration of the NMDAR pore. Further analysis of important regions of the NMDAR protein such as pore surface (M2 α-helix), Mg 2+ binding site, and TMD-M4 α-helix revealed significant effects of helium. In contrast with previous models, these and our earlier results suggest that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions. Helium in divers' breathing mixtures may partially contribute to HPNS symptoms. To provide background information regarding the underlying biological mechanisms of high pressure physiology, we feel it necessary to reiterate the main concepts and experimental findings described in our previous studies 1-3. Military and occupational divers who engage in deep diving reach depths greater than 50 m sea water, and are thus exposed to pressures above 6 atmospheres absolute (ATA) or 6 bar, where 1 bar ≅ 10 m sea water. Professional divers in the oil industry perform underwater construction work at an average depth of 200 m. In 1988, professional divers employed by the Comex diving company in the Mediterranean Sea performed the deepest known working dive at a depth of 534 m (53.7 bar) 4. The deepest known test dive in a dry pressure chamber, to a depth of 701 m (70.5 bar) was carried out at the Comex facility in France in 1992 5. To avoid oxygen toxicity and nitrogen narcosis, deep divers use a breathing gas mixture known as trimix, which contains varying percentages of oxygen, nitrogen and helium. Pressures as high as these present the divers' lungs, viscera, and particularly the nervous system, with a considerable physiological challenge. Diving deeper than 11 bar may result in the high pressure neurological syndrome (HPNS) 6 , which is characterized by cognitive and motor deficits and reversible central nervous system (CNS) hyperexcitability. As observed in humans and in animal models, susceptibility to HPNS depends on the compression rate and the absolute ambient pressure at the maximal maintained depth. The majority of signs and symptoms in HPNS have their origin in disturbances of CNS synaptic activity 7. Apart from the symptoms which appear during a dive and are usually reversible, professional divers who engage in repetitive deep sea operations over a period of years may also develop permanent memory and motor impairment 8. In recent years, the activity of N-methyl-D-aspartate receptors (NMDARs) has been discovered as one of the main underlying mechanisms of CNS hyperexcitability at hight pressure and the symptoms of HPNS 9-14. NMDARs are responsible for mediating excitatory synaptic transmission within the CNS 15. They belong to the family of ionotropic glutamate receptors and have 14 different structural subunits. The GluN1 family is encoded by one gene and may present eight different subunits due to alternative RNA splicing mechanisms 16 : GluN1-1a 1 israel naval Medical institute, Haifa, israel.

Physical Chemistry Chemical Physics, 2014

This paper presents a study of protein adsorption and denaturation using coarse-grained Monte Car... more This paper presents a study of protein adsorption and denaturation using coarse-grained Monte Carlo simulations with simulated annealing. Intermolecular interactions are modeled using the Miyazawa-Jernigan (MJ) knowledge-based potential for an implicit solvent. Three different hydrophobicity scales are tested for adsorption of fibronectin on a hydrophobic surface. The hydrophobic scale BULDG was chosen for further analysis due to its greater stability during heating and its partial regenerative ability upon slow cooling. Differences between helical and sheet structures are observed upon denaturation -α-helices undergo spreading of their native helical order to an elliptical perturbed shape, while β-sheets transform into random coils and other more structured conformations. Electronic calculations carried out on rebuilt all-atom coordinates of adsorbed lysozymes revealed consistent destabilization of helices, while beta sheets show a greater variety of trends.

Physical Chemistry Chemical Physics, 2012

A coarse-grained Monte Carlo simulation is used to study thermal denaturation of small proteins i... more A coarse-grained Monte Carlo simulation is used to study thermal denaturation of small proteins in an infinitely dilute solution and adsorbed on a flat hydrophobic surface. Intermolecular interactions are modeled using the Miyazawa-Jernigan (MJ) knowledge-based potential for implicit solvent with the BULDG hydrophobicity scale. We analyze the thermal behavior of lysozyme for its prevalence of α-helices, fibronectin for its prevalence of β-sheets, and a short single helical peptide. Protein dimensions and contact maps are studied in detail before and during isothermal adsorption and heating. The MJ potential is shown to correctly predict the native conformation in solution under standard conditions, and the anticipated thermal stabilization of adsorbed proteins is observed when compared with heating in solution. The helix of the peptide is found to be much less stable thermally than the helices of lysozyme, reinforcing the importance of long-range forces in defining the protein structure. Contact map analysis of the adsorbed proteins shows correlation between the hydrophobicity of the secondary structure and their thermal stability on the surface.

Our objective was to study molecular processes that might be responsible for inert gas narcosis a... more Our objective was to study molecular processes that might be responsible for inert gas narcosis and highpressure nervous syndrome. The classical molecular dynamics trajectories (200 ns) of dioleoylphosphatidylcholine (DOPC) bilayers simulated by the Berger force field were evaluated for water and the atomic distribution of noble gases around DOPC molecules in the pressure range of 1-1000 bar and at a temperature of 310 K. Xenon and argon have been tested as model gases for general anaesthetics, and neon has been investigated for distortions that are potentially responsible for neurological tremors in hyperbaric conditions. The analysis of stacked radial pair distribution functions of DOPC headgroup atoms revealed the explicit solvation potential of the gas molecules, which correlates with their dimensions. The orientational dynamics of water molecules at the biomolecular interface should be considered as an influential factor, while excessive solvation effects appearing in the lumen of membrane-embedded ion channels could be a possible cause of inert gas narcosis. All the noble gases tested exhibit similar order parameter patterns for both DOPC acyl chains, which are opposite of the patterns found for the order parameter curve at high hydrostatic pressures in intact bilayers. This finding supports the 'critical volume' hypothesis of anaesthesia pressure reversal. The irregular lipid headgroupwater boundary observed in DOPC bilayers saturated with neon in the pressure range of 1-100 bar could be associated with the possible manifestation of neurological tremors at the atomic scale. The non-immobiliser neon also demonstrated the highest momentum impact on the normal component of the DOPC diffusion coefficient representing the monolayer undulation rate, which indicates that enhanced diffusivity rather than atomic size is the key factor.

Biophysical Journal, 2005

Two-dimensional mean-field lattice theory is used to model immobilization and stabilization of an... more Two-dimensional mean-field lattice theory is used to model immobilization and stabilization of an enzyme on a hydrophobic surface using grafted polymers. Although the enzyme affords biofunctionality, the grafted polymers stabilize the enzyme and impart biocompatibility. The protein is modeled as a compact hydrophobic-polar polymer, designed to have a specific bulk conformation reproducing the catalytic cleft of natural enzymes. Three scenarios are modeled that have medical or industrial importance: 1), It is shown that short hydrophilic grafted polymers, such as polyethylene glycol, which are often used to provide biocompatibility, can also serve to protect a surface-immobilized enzyme from adsorption and denaturation on a hydrophobic surface. 2), Screening of the enzyme from the surface and nonspecific interactions with biomaterial in bulk solution requires a grafted layer composed of short hydrophilic polymers and long triblock copolymers. 3), Hydrophilic polymers grafted on a hydrophobic surface in contact with an organic solvent form a dense hydrophilic nanoenvironment near the surface that effectively shields and stabilizes the enzyme against both surface and solvent.

Physical Review E, 2004

We introduce a two-dimensional lattice model of immobilization and stabilization of proteinlike p... more We introduce a two-dimensional lattice model of immobilization and stabilization of proteinlike polymers using grafted polymers. The protein is designed to have a specific bulk conformation reproducing a catalytic cleft of natural enzymes. Our model predicts a first order denaturing adsorption transition of free proteins. On the other hand, for an immobilized protein we observe a more gradual disappearance of the hydrophobic centers accompanied by adsorption. We show that, using hydrophilic grafted polymers of proper length and grafting density, the conformation as well as the hydrophobic centers of the protein can be restored.

Arieli, R., and Y. Moskovitz. Humidity does not affect central nervous system oxygen toxicity. J ... more Arieli, R., and Y. Moskovitz. Humidity does not affect central nervous system oxygen toxicity. J Appl Physiol 91: [1327][1328][1329][1330][1331][1332][1333] 2001.-Central nervous system (CNS) oxygen toxicity can occur as convulsions and loss of consciousness when hyperbaric oxygen is breathed in diving and hyperbaric medical therapy. Lin and Jamieson (J Appl Physiol 75: 1980-1983 reported that humidity in the inspired gas enhances CNS oxygen toxicity. Because alveolar gas is fully saturated with water vapor, we could not see a cause and effect and surmised that other factors, such as metabolic rate, might be involved. Rats were exposed to 507-and 608-kPa O2 in dry (31 or 14%) or humid (99%) atmosphere until the appearance of the first electrical discharge preceding the clinical convulsions. Each rat served as its own control. A thermoneutral temperature (28 Ϯ 0.4°C) yielded resting CO2 production of 0.81 Ϯ 0.06 ml ⅐ g Ϫ1 ⅐ h Ϫ1 . Latency to the first electrical discharge was not affected by humidity. At 507-kPa O2, latency was 23 Ϯ 0.4 and 22 Ϯ 0.7 min in dry and humid conditions, respectively, and, at 608-kPa O2, latency was 15 Ϯ 4 and 14 Ϯ 3 min in dry and humid conditions, respectively. When no effects of CO2 and metabolic rate are present, humidity does not affect CNS oxygen toxicity. Relevance of the findings to diving and hyperbaric therapy is discussed. hyperbaric oxygen; metabolic rate; electroencephalograph; rat; carbon dioxide

Arieli, R., G. Rashkovan, Y. Moskovitz, and O. Ertracht. PCO 2 threshold for CNS oxygen toxicity ... more Arieli, R., G. Rashkovan, Y. Moskovitz, and O. Ertracht. PCO 2 threshold for CNS oxygen toxicity in rats in the low range of hyperbaric PO2. J Appl Physiol 91: [1582][1583][1584][1585][1586][1587] 2001.-Central nervous system (CNS) oxygen toxicity, as manifested by the first electrical discharge (FED) in the electroencephalogram, can occur as convulsions and loss of consciousness. CO 2 potentiates this risk by vasodilation and pH reduction. We suggest that CO2 can produce CNS oxygen toxicity at a PO2 that does not on its own ultimately cause FED. We searched for the CO2 threshold that will result in the appearance of FED at a PO2 between 507 and 253 kPa. Rats were exposed to a PO2 and an inspired PCO2 in 1-kPa steps to define the threshold for FED. The results confirmed our assumption that each rat has its own PCO2 threshold, any PCO2 above which will cause FED but below which no FED will occur. As PO2 decreased from 507 to 456, 405, and 355 kPa, the percentage of rats that exhibited FED without the addition of CO2 (F0) dropped from 91 to 62, to 8 and 0%, respectively. The percentage of rats (F) having FED as a function of PCO2 was sigmoid in shape and displaced toward high PCO2 with the reduction in PO2. The following formula is suggested to express risk as a function of PCO2 and PO2

Physical Chemistry Chemical Physics, 2014

Physical Chemistry Chemical Physics, 2012

Biophysical Journal, 2005

Physical Review E, 2004