International Journal of Molecular Sciences

402 KiB

Open AccessArticle

AFM and Multiple Transmission-Reflection Infrared Spectroscopy (MTR-IR) Studies on Formation of Air-Stable Supported Lipid Bilayers

by Peng-Feng Guo, Wen-Yi Huang, Hong-Bo Liu and Shou-Jun Xiao

Int. J. Mol. Sci. 2009, 10(3), 1407-1418; https://doi.org/10.3390/ijms10031407 - 26 Mar 2009

Cited by 5 | Viewed by 14715

Abstract

Supported lipid bilayers (SLBs) were prepared by deposition of unilamellar vesicles on a silicon substrate. Atomic force microscopy (AFM) and a new Multiple Transmission-Reflection Infrared Spectroscopy (MTR-IR) developed by us were used to trace the dynamic formation of lipid bilayers on the silicon [...] Read more.

Supported lipid bilayers (SLBs) were prepared by deposition of unilamellar vesicles on a silicon substrate. Atomic force microscopy (AFM) and a new Multiple Transmission-Reflection Infrared Spectroscopy (MTR-IR) developed by us were used to trace the dynamic formation of lipid bilayers on the silicon surfaces. The evolution from deformation of vesicles to formation of bilayers can be distinguished clearly by AFM imaging. MTR-IR provided high quality infrared spectra of ultrathin lipid bilayers with high sensitivity and high signal to noise ratio (SNR). The structural and orientational changes during vesicle’s fusion were monitored with MTR-IR. MTR-IR shows superiority over other infrared approaches for ultrathin films on standard silicon wafers in view of its economy and high sensitivity. Both MTR-IR and AFM results were consistent with each other and they provided more information for understanding the self-assembling procedure of SLBs. Full article

(This article belongs to the Special Issue Molecular Self-Assembly)

► Show Figures

Graphical abstract

239 KiB

Open AccessReview

Molecular Pathogenesis of Alzheimer’s Disease: Reductionist versus Expansionist Approaches

by Rudy J. Castellani, Xiongwei Zhu, Hyoung-Gon Lee, Mark A. Smith and George Perry

Int. J. Mol. Sci. 2009, 10(3), 1386-1406; https://doi.org/10.3390/ijms10031386 - 26 Mar 2009

Cited by 39 | Viewed by 15824

Abstract

Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as [...] Read more.

Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as substantial optimism about successful therapeutic intervention. In 2009, we now have copious knowledge on the biochemical cascades that produce these proteins, the different modifications and forms in which these proteins exist, and the ability to selectively target these proteins for therapeutic intervention on an experimental basis. At the same time, there has been no discernible alteration in the natural course of AD in humans. While it may be that the complexity of AD will exceed our capacity to make significant treatment progress for decades or more, a paradigm shift from the reductionism that defines amyloid-β and tau hypotheses, to one that more accurately reflects the meaning of neuropathological changes, may be warranted. We and others have demonstrated that AD pathology is a manifestation of cellular adaptation, specifically as a defense against oxidative injury. As such, AD pathology is therefore a host response rather than a manifestation of cytotoxic protein injury, and is unlikely to be a fruitful target for therapeutic intervention. An “expansionist” view of the disease, we believe, with oxidative stress as a pleiotropic and upstream process, more aptly describes the relationship between various and numerous molecular alterations and clinical disease. Full article

(This article belongs to the Special Issue Advances in Molecular Neuropathology)

250 KiB

Open AccessReview

Slow Unfolding of Monomeric Proteins from Hyperthermophiles with Reversible Unfolding

by Atsushi Mukaiyama and Kazufumi Takano

Int. J. Mol. Sci. 2009, 10(3), 1369-1385; https://doi.org/10.3390/ijms10031369 - 24 Mar 2009

Cited by 16 | Viewed by 13572

Abstract

Based on the differences in their optimal growth temperatures microorganisms can be classified into psychrophiles, mesophiles, thermophiles, and hyperthermophiles. Proteins from hyperthermophiles generally exhibit greater stability than those from other organisms. In this review, we collect data about the stability and folding of [...] Read more.

Based on the differences in their optimal growth temperatures microorganisms can be classified into psychrophiles, mesophiles, thermophiles, and hyperthermophiles. Proteins from hyperthermophiles generally exhibit greater stability than those from other organisms. In this review, we collect data about the stability and folding of monomeric proteins from hyperthermophilies with reversible unfolding, from the equilibrium and kinetic aspects. The results indicate that slow unfolding is a general strategy by which proteins from hyperthermophiles adapt to higher temperatures. Hydrophobic interaction is one of the factors in the molecular mechanism of the slow unfolding of proteins from hyperthermophiles. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

164 KiB

Open AccessEditorial

Protein Dynamics: From Molecules, to Interactions, to Biology

by Martin Gruebele

Int. J. Mol. Sci. 2009, 10(3), 1360-1368; https://doi.org/10.3390/ijms10031360 - 20 Mar 2009

Cited by 4 | Viewed by 12021

Abstract

Proteins have a remarkably rich diversity of dynamical behaviors, and the articles in this issue of the International Journal of Molecular Sciences are a testament to that fact. From the picosecond motions of single sidechains probed by NMR or fluorescence spectroscopy, to aggregation [...] Read more.

Proteins have a remarkably rich diversity of dynamical behaviors, and the articles in this issue of the International Journal of Molecular Sciences are a testament to that fact. From the picosecond motions of single sidechains probed by NMR or fluorescence spectroscopy, to aggregation processes at interfaces that take months, all time scales play a role. Proteins are functional molecules, so by their nature they always interact with their environment. This environment includes water, other biomolecules, or larger cellular structures. In a sense, it also includes the protein molecule itself: proteins are large enough to fold and interact with themselves. These interactions have been honed by evolution to produce behaviors completely different from those of random polymers. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

249 KiB

Open AccessReview

Participation of Low Molecular Weight Electron Carriers in Oxidative Protein Folding

by Éva Margittai, Miklós Csala, József Mandl and Gábor Bánhegyi

Int. J. Mol. Sci. 2009, 10(3), 1346-1359; https://doi.org/10.3390/ijms10031346 - 20 Mar 2009

Cited by 8 | Viewed by 14807

Abstract

Oxidative protein folding is mediated by a proteinaceous electron relay system, in which the concerted action of protein disulfide isomerase and Ero1 delivers the electrons from thiol groups to the final acceptor. Oxygen appears to be the final oxidant in aerobic living organisms, [...] Read more.

Oxidative protein folding is mediated by a proteinaceous electron relay system, in which the concerted action of protein disulfide isomerase and Ero1 delivers the electrons from thiol groups to the final acceptor. Oxygen appears to be the final oxidant in aerobic living organisms, although the existence of alternative electron acceptors, e.g. fumarate or nitrate, cannot be excluded. Whilst the protein components of the system are well-known, less attention has been turned to the role of low molecular weight electron carriers in the process. The function of ascorbate, tocopherol and vitamin K has been raised recently. In vitro and in vivo evidence suggests that these redox-active compounds can contribute to the functioning of oxidative folding. This review focuses on the participation of small molecular weight redox compounds in oxidative protein folding. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

474 KiB

Open AccessReview

Mechanism of Suppression of Protein Aggregation by α-Crystallin

by Kira A. Markossian, Igor K. Yudin and Boris I. Kurganov

Int. J. Mol. Sci. 2009, 10(3), 1314-1345; https://doi.org/10.3390/ijms10031314 - 19 Mar 2009

Cited by 50 | Viewed by 23981

Abstract

This review summarizes experimental data illuminating the mechanism of suppression of heat-induced protein aggregation by a-crystallin, one of the small heat shock proteins. The dynamic light scattering data show that the initial stage of thermal aggregation of proteins is the formation of the [...] Read more.

This review summarizes experimental data illuminating the mechanism of suppression of heat-induced protein aggregation by a-crystallin, one of the small heat shock proteins. The dynamic light scattering data show that the initial stage of thermal aggregation of proteins is the formation of the initial aggregates involving hundreds of molecules of the denatured protein. Further sticking of the starting aggregates proceeds in a regime of diffusion-limited cluster-cluster aggregation. The protective effect of a-crystallin is due to transition of the aggregation process to the regime of reaction-limited cluster-cluster aggregation, wherein the sticking probability for the colliding particles becomes lower than unity. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

Graphical abstract

132 KiB

Open AccessReview

In Vitro Models in Biocompatibility Assessment for Biomedical-Grade Chitosan Derivatives in Wound Management

by Lim Chin Keong and Ahmad Sukari Halim

Int. J. Mol. Sci. 2009, 10(3), 1300-1313; https://doi.org/10.3390/ijms10031300 - 18 Mar 2009

Cited by 128 | Viewed by 16377

Abstract

One of the ultimate goals of wound healing research is to find effective healing techniques that utilize the regeneration of similar tissues. This involves the modification of various wound dressing biomaterials for proper wound management. The biopolymer chitosan (b-1,4-D-glucosamine) has natural biocompatibility and [...] Read more.

One of the ultimate goals of wound healing research is to find effective healing techniques that utilize the regeneration of similar tissues. This involves the modification of various wound dressing biomaterials for proper wound management. The biopolymer chitosan (b-1,4-D-glucosamine) has natural biocompatibility and biodegradability that render it suitable for wound management. By definition, a biocompatible biomaterial does not have toxic or injurious effects on biological systems. Chemical and physical modifications of chitosan influence its biocompatibility and biodegradability to an uncertain degree. Hence, the modified biomedical-grade of chitosan derivatives should be pre-examined in vitro in order to produce high-quality, biocompatible dressings. In vitro toxicity examinations are more favorable than those performed in vivo, as the results are more reproducible and predictive. In this paper, basic in vitro tools were used to evaluate cellular and molecular responses with regard to the biocompatibility of biomedical-grade chitosan. Three paramount experimental parameters of biocompatibility in vitro namely cytocompatibility, genotoxicity and skin pro-inflammatory cytokine expression, were generally reviewed for biomedical-grade chitosan as wound dressing. Full article

(This article belongs to the Special Issue Biocompatibility of Materials)

187 KiB

Open AccessArticle

Origin of Homochirality in Biosystems

by Søren Toxvaerd

Int. J. Mol. Sci. 2009, 10(3), 1290-1299; https://doi.org/10.3390/ijms10031290 - 18 Mar 2009

Cited by 34 | Viewed by 12083

Abstract

Experimental data for a series of central and simple molecules in biosystems show that some amino acids and a simple sugar molecule have a chiral discrimination in favor of homochirality. Models for segregation of racemic mixtures of chiral amphiphiles and lipophiles in aqueous [...] Read more.

Experimental data for a series of central and simple molecules in biosystems show that some amino acids and a simple sugar molecule have a chiral discrimination in favor of homochirality. Models for segregation of racemic mixtures of chiral amphiphiles and lipophiles in aqueous solutions show that the amphiphiles with an active isomerization kinetics can perform a spontaneous break of symmetry during the segregation and self-assembly to homochiral matter. Based on this observation it is argued that biomolecules with a sufficiently strong chiral discrimination could be the origin of homochirality in biological systems. Full article

(This article belongs to the Special Issue Origin of Life)

► Show Figures

314 KiB

Open AccessArticle

Explaining Ionic Liquid Water Solubility in Terms of Cation and Anion Hydrophobicity

by Johannes Ranke, Alaa Othman, Ping Fan and Anja Müller

Int. J. Mol. Sci. 2009, 10(3), 1271-1289; https://doi.org/10.3390/ijms10031271 - 18 Mar 2009

Cited by 121 | Viewed by 20221

Abstract

The water solubility of salts is ordinarily dictated by lattice energy and ion solvation. However, in the case of low melting salts also known as ionic liquids, lattice energy is immaterial and differences in hydrophobicity largely account for differences in their water solubility. [...] Read more.

The water solubility of salts is ordinarily dictated by lattice energy and ion solvation. However, in the case of low melting salts also known as ionic liquids, lattice energy is immaterial and differences in hydrophobicity largely account for differences in their water solubility. In this contribution, the activity coefficients of ionic liquids in water are split into cation and anion contributions by regression against cation hydrophobicity parameters that are experimentally determined by reversed phase liquid chromatography. In this way, anion hydrophobicity parameters are derived, as well as an equation to estimate water solubilities for cation-anion combinations for which the water solubility has not been measured. Thus, a new pathway to the quantification of aqueous ion solvation is shown, making use of the relative weakness of interactions between ionic liquid ions as compared to their hydrophobicities. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

► Show Figures

Graphical abstract

275 KiB

Open AccessArticle

Dielectric Properties of Binary Solvent Mixtures of Dimethyl Sulfoxide with Water

by Li-Jun Yang, Xiao-Qing Yang, Ka-Ma Huang, Guo-Zhu Jia and Hui Shang

Int. J. Mol. Sci. 2009, 10(3), 1261-1270; https://doi.org/10.3390/ijms10031261 - 17 Mar 2009

Cited by 65 | Viewed by 15495

Abstract

In this paper, the dielectric properties of water-dimethylsulfoxide (DMSO) mixtures with different mole ratios have been investigated in the range of 1 GHz to 40 GHz at 298 K by using a molecular dynamics (MD) simulation. Only one dielectric loss peak was observed [...] Read more.

In this paper, the dielectric properties of water-dimethylsulfoxide (DMSO) mixtures with different mole ratios have been investigated in the range of 1 GHz to 40 GHz at 298 K by using a molecular dynamics (MD) simulation. Only one dielectric loss peak was observed in the frequency range and the relaxation in these mixtures can be described by a single relaxation time of the Davidson-Cole. It was observed that within experimental error the dielectric relaxation can be described by the Debye-like model (β ≈ 1, S.M. Puranik, et al. J. Chem. Soc. Faraday Trans.1992, 88, 433 - 435). In general, the results are very consistent with the experimental measurements. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

► Show Figures

307 KiB

Open AccessReview

Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

by David Olivares, Xudong Huang, Lars Branden, Nigel H. Greig and Jack T. Rogers

Int. J. Mol. Sci. 2009, 10(3), 1226-1260; https://doi.org/10.3390/ijms10031226 - 17 Mar 2009

Cited by 72 | Viewed by 21674

Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer's disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein [...] Read more.

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer's disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn) has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target. Full article

(This article belongs to the Special Issue Advances in Molecular Neuropathology)

► Show Figures

358 KiB

Open AccessArticle

Ultra Low-Dose Radiation: Stress Responses and Impacts Using Rice as a Grass Model

by Randeep Rakwal, Ganesh Kumar Agrawal, Junko Shibato, Tetsuji Imanaka, Satoshi Fukutani, Shigeru Tamogami, Satoru Endo, Sarata Kumar Sahoo Sahoo, Yoshinori Masuo and Shinzo Kimura

Int. J. Mol. Sci. 2009, 10(3), 1215-1225; https://doi.org/10.3390/ijms10031215 - 16 Mar 2009

Cited by 18 | Viewed by 14070

Abstract

We report molecular changes in leaves of rice plants (Oryza sativa L. - reference crop plant and grass model) exposed to ultra low-dose ionizing radiation, first using contaminated soil from the exclusion zone around Chernobyl reactor site. Results revealed induction of stress-related [...] Read more.

We report molecular changes in leaves of rice plants (Oryza sativa L. - reference crop plant and grass model) exposed to ultra low-dose ionizing radiation, first using contaminated soil from the exclusion zone around Chernobyl reactor site. Results revealed induction of stress-related marker genes (Northern blot) and secondary metabolites (LC-MS/MS) in irradiated leaf segments over appropriate control. Second, employing the same in vitro model system, we replicated results of the first experiment using in-house fabricated sources of ultra low-dose gamma (g) rays and selected marker genes by RT-PCR. Results suggest the usefulness of the rice model in studying ultra low-dose radiation response/s. Full article

(This article belongs to the Special Issue Biotic and Abiotic Stress)

► Show Figures

295 KiB

Open AccessArticle

Quantum-SAR Extension of the Spectral-SAR Algorithm. Application to Polyphenolic Anticancer Bioactivity

by Mihai V. Putz, Ana-Maria Putz, Marius Lazea, Luciana Ienciu and Adrian Chiriac

Int. J. Mol. Sci. 2009, 10(3), 1193-1214; https://doi.org/10.3390/ijms10031193 - 16 Mar 2009

Cited by 40 | Viewed by 13918

Abstract

Aiming to assess the role of individual molecular structures in the molecular mechanism of ligand-receptor interaction correlation analysis, the recent Spectral-SAR approach is employed to introduce the Quantum-SAR (QuaSAR) “wave” and “conversion factor” in terms of difference between inter-endpoint inter-molecular activities for a [...] Read more.

Aiming to assess the role of individual molecular structures in the molecular mechanism of ligand-receptor interaction correlation analysis, the recent Spectral-SAR approach is employed to introduce the Quantum-SAR (QuaSAR) “wave” and “conversion factor” in terms of difference between inter-endpoint inter-molecular activities for a given set of compounds; this may account for inter-conversion (metabolization) of molecular (concentration) effects while indicating the structural (quantum) based influential/detrimental role on bio-/eco- effect in a causal manner rather than by simple inspection of measured values; the introduced QuaSAR method is then illustrated for a study of the activity of a series of flavonoids on breast cancer resistance protein. Full article

(This article belongs to the Special Issue Recent Advances in QSAR/QSPR Theory)

► Show Figures

1541 KiB

Open AccessReview

Philosophical Basis and Some Historical Aspects of Systems Biology: From Hegel to Noble - Applications for Bioenergetic Research

by Valdur Saks, Claire Monge and Rita Guzun

Int. J. Mol. Sci. 2009, 10(3), 1161-1192; https://doi.org/10.3390/ijms10031161 - 13 Mar 2009

Cited by 42 | Viewed by 19035

Abstract

We live in times of paradigmatic changes for the biological sciences. Reductionism, that for the last six decades has been the philosophical basis of biochemistry and molecular biology, is being displaced by Systems Biology, which favors the study of integrated systems. Historically, Systems [...] Read more.

We live in times of paradigmatic changes for the biological sciences. Reductionism, that for the last six decades has been the philosophical basis of biochemistry and molecular biology, is being displaced by Systems Biology, which favors the study of integrated systems. Historically, Systems Biology - defined as the higher level analysis of complex biological systems - was pioneered by Claude Bernard in physiology, Norbert Wiener with the development of cybernetics, and Erwin Schrödinger in his thermodynamic approach to the living. Systems Biology applies methods inspired by cybernetics, network analysis, and non-equilibrium dynamics of open systems. These developments follow very precisely the dialectical principles of development from thesis to antithesis to synthesis discovered by Hegel. Systems Biology opens new perspectives for studies of the integrated processes of energy metabolism in different cells. These integrated systems acquire new, system-level properties due to interaction of cellular components, such as metabolic compartmentation, channeling and functional coupling mechanisms, which are central for regulation of the energy fluxes. State of the art of these studies in the new area of Molecular System Bioenergetics is analyzed. Full article

(This article belongs to the Special Issue Molecular System Bioenergetics)

► Show Figures

644 KiB

Open AccessArticle

Changes in Metallothionein Level in Rat Hepatic Tissue after Administration of Natural Mouldy Wheat

by Anna Vasatkova, Sarka Krizova, Vojtech Adam, Ladislav Zeman and Rene Kizek

Int. J. Mol. Sci. 2009, 10(3), 1138-1160; https://doi.org/10.3390/ijms10031138 - 12 Mar 2009

Cited by 20 | Viewed by 13049

Abstract

Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals. This work was aimed at investigation of influence of mouldy wheat contaminated by pathogenic fungi producing mycotoxins on metallothionein levels in hepatic tissue [...] Read more.

Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals. This work was aimed at investigation of influence of mouldy wheat contaminated by pathogenic fungi producing mycotoxins on metallothionein levels in hepatic tissue of rats. The rats were administrating feed mixtures with different contents of vitamins or naturally mouldy wheat for 28 days. It was found that the wheat contained deoxynivalenol (80 ± 5 µg per kg of mouldy wheat), zearalenone (56 ± 3 µg/kg), T2-toxin (20 ± 2 µg/kg) and aflatoxins as a sum of B1, B2, G1 and G2 (3.9 ± 0.2 µg/kg). Rats were fed diets containing 0, 33, 66 and 100% naturally moulded wheat. Control group 0, 33, 66 and 100% contained vitamins according to Nutrient Requirements of Rats (NRC). Other four groups (control group with vitamins, vit33, vit66 and vit100%) were fed on the same levels of mouldy wheat, also vitamins at levels 100% higher than the previous mixtures. We determined weight, feed conversion and performed dissection to observe pathological processes. Changes between control group and experimental groups exposed to influence of mouldy wheat and experimental groups supplemented by higher concentration of vitamins and mouldy wheat were not observed. Livers were sampled and did not demonstrate significant changes in morphology compared to control either. In the following experiments the levels of metallothionein as a marker of oxidative stress was determined. We observed a quite surprising trend in metallothionein levels in animals supplemented with increased concentration of vitamins. Its level enhanced with increasing content of mouldy wheat. It was possible to determine a statistically significant decline (p<0.05) between control group and groups of animals fed with 33, 66 and 100% mouldy wheat. It is likely that some mycotoxins presented in mouldy wheat are able to block the mechanism of metallothionein synthesis. Full article

(This article belongs to the Special Issue Mycotoxins: Mechanisms of Toxicological Activity - Treatment and Prevention)

► Show Figures

553 KiB

Open AccessArticle

Folding of Trp-cage Mini Protein Using Temperature and Biasing Potential Replica—Exchange Molecular Dynamics Simulations

by Srinivasaraghavan Kannan and Martin Zacharias

Int. J. Mol. Sci. 2009, 10(3), 1121-1137; https://doi.org/10.3390/ijms10031121 - 12 Mar 2009

Cited by 18 | Viewed by 17255

Abstract

The folding process of the 20 residue Trp-cage mini-protein was investigated using standard temperature replica exchange molecular dynamics (T-RexMD) simulation and a biasing potential RexMD (BP-RexMD) method. In contrast to several conventional molecular dynamics simulations, both RexMD methods sampled conformations close to the [...] Read more.

The folding process of the 20 residue Trp-cage mini-protein was investigated using standard temperature replica exchange molecular dynamics (T-RexMD) simulation and a biasing potential RexMD (BP-RexMD) method. In contrast to several conventional molecular dynamics simulations, both RexMD methods sampled conformations close to the native structure after 10-20 ns simulation time as the dominant conformational states. In contrast, to T-RexMD involving 16 replicas the BP-RexMD method achieved very similar sampling results with only five replicas. The result indicates that the BP-RexMD method is well suited to study folding processes of proteins at a significantly smaller computational cost, compared to T-RexMD. Both RexMD methods sampled not only similar final states but also agreed on the sampling of intermediate conformations during Trp-cage folding. The analysis of the sampled potential energy contributions indicated that Trp-cage folding is favored by both van der Waals and to a lesser degree electrostatic contributions. Folding does not introduce any significant sterical strain as reflected by similar energy distributions of bonded energy terms (bond length, bond angle and dihedral angle) of folded and unfolded Trp-cage structures. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

Graphical abstract

500 KiB

Open AccessArticle

Calcium Ions Regulate K+ Uptake into Brain Mitochondria: The Evidence for a Novel Potassium Channel

by Jolanta Skalska, Piotr Bednarczyk, Marta Piwońska, Bogusz Kulawiak, Grzegorz Wilczynski, Krzysztof Dołowy, Wolfram S. Kunz, Alexei P. Kudin and Adam Szewczyk

Int. J. Mol. Sci. 2009, 10(3), 1104-1120; https://doi.org/10.3390/ijms10031104 - 12 Mar 2009

Cited by 76 | Viewed by 14894

Abstract

The mitochondrial response to changes of cytosolic calcium concentration has a strong impact on neuronal cell metabolism and viability. We observed that Ca²⁺ additions to isolated rat brain mitochondria induced in potassium ion containing media a mitochondrial membrane potential depolarization and an [...] Read more.

The mitochondrial response to changes of cytosolic calcium concentration has a strong impact on neuronal cell metabolism and viability. We observed that Ca²⁺ additions to isolated rat brain mitochondria induced in potassium ion containing media a mitochondrial membrane potential depolarization and an accompanying increase ofmitochondrial respiration. These Ca²⁺ effects can be blocked by iberiotoxin and charybdotoxin, well known inhibitors of large conductance potassium channel (BK_Ca channel). Furthermore, NS1619 – a BK_Ca channel opener – induced potassium ion–specific effects on brain mitochondria similar to those induced by Ca²⁺. These findings suggest the presence of a calcium-activated, large conductance potassium channel (sensitive to charybdotoxin and NS1619), which was confirmed by reconstitution of the mitochondrial inner membrane into planar lipid bilayers. The conductance of the reconstituted channel was 265 pS under gradient (50/450 mM KCl) conditions. Its reversal potential was equal to 50 mV, which proved that the examined channel was cation-selective. We also observed immunoreactivity of anti-b₄ subunit (of the BK_Ca channel) antibodies with ~26 kDa proteins of rat brain mitochondria. Immunohistochemical analysis confirmed the predominant occurrence of b₄ subunit in neuronal mitochondria. We hypothesize that the mitochondrial BK_Ca channel represents a calcium sensor, which can contribute to neuronal signal transduction and survival. Full article

(This article belongs to the Special Issue Molecular System Bioenergetics)

► Show Figures

169 KiB

Open AccessArticle

Dietary Protection Against Free Radicals: A Case for Multiple Testing to Establish Structure-activity Relationships for Antioxidant Potential of Anthocyanic Plant Species

by Martin Philpott, Chiara Cheng Lim and Lynnette R. Ferguson

Int. J. Mol. Sci. 2009, 10(3), 1081-1103; https://doi.org/10.3390/ijms10031081 - 11 Mar 2009

Cited by 33 | Viewed by 16458

Abstract

DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing [...] Read more.

DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl- radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0^oC, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37^oC, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays. Full article

(This article belongs to the Special Issue Structure-Property/Activity Modeling of Polyphenols)

► Show Figures

287 KiB

Open AccessReview

Importance of Translational Entropy of Water in Biological Self-Assembly Processes like Protein Folding

by Masahiro Kinoshita

Int. J. Mol. Sci. 2009, 10(3), 1064-1080; https://doi.org/10.3390/ijms10031064 - 11 Mar 2009

Cited by 72 | Viewed by 13649

Abstract

We briefly review our studies on the folding/unfolding mechanisms of proteins. In biological self-assembly processes such as protein folding, the number of accessible translational configurations of water in the system increases greatly, leading to a large gain in the water entropy. The usual [...] Read more.

We briefly review our studies on the folding/unfolding mechanisms of proteins. In biological self-assembly processes such as protein folding, the number of accessible translational configurations of water in the system increases greatly, leading to a large gain in the water entropy. The usual view looking at only the water in the close vicinity of the protein surface is capable of elucidating neither the large entropic gain upon apoplastocyanin folding, which has recently been found in a novel experimental study, nor the pressure and cold denaturation. With the emphasis on the translational entropy of water, we are presently constructing a reliable method for predicting the native structure of a protein from its amino-acid sequence. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

655 KiB

Open AccessReview

Molecular Pathology of Neuro-AIDS (CNS-HIV)

by Leslie Crews, Christina Patrick, Cristian L. Achim, Ian P. Everall and Eliezer Masliah

Int. J. Mol. Sci. 2009, 10(3), 1045-1063; https://doi.org/10.3390/ijms10031045 - 11 Mar 2009

Cited by 61 | Viewed by 18335

Abstract

The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE). With the advent of more effective anti-retroviral therapies, HIVE has [...] Read more.

The cognitive deficits in patients with HIV profoundly affect the quality of life of people living with this disease and have often been linked to the neuro-inflammatory condition known as HIV encephalitis (HIVE). With the advent of more effective anti-retroviral therapies, HIVE has shifted from a sub-acute to a chronic condition. The neurodegenerative process in patients with HIVE is characterized by synaptic and dendritic damage to pyramidal neurons, loss of calbindin-immunoreactive interneurons and myelin loss. The mechanisms leading to neurodegeneration in HIVE might involve a variety of pathways, and several lines of investigation have found that interference with signaling factors mediating neuroprotection might play an important role. These signaling pathways include, among others, the GSK3b, CDK5, ERK, Pyk2, p38 and JNK cascades. Of these, GSK3b has been a primary focus of many previous studies showing that in infected patients, HIV proteins and neurotoxins secreted by immune-activated cells in the brain abnormally activate this pathway, which is otherwise regulated by growth factors such as FGF. Interestingly, modulation of the GSK3b signaling pathway by FGF1 or GSK3b inhibitors (lithium, valproic acid) is protective against HIV neurotoxicity, and several pilot clinical trials have demonstrated cognitive improvements in HIV patients treated with GSK3b inhibitors. In addition to the GSK3b pathway, the CDK5 pathway has recently been implicated as a mediator of neurotoxicity in HIV, and HIV proteins might activate this pathway and subsequently disrupt the diverse processes that CDK5 regulates, including synapse formation and plasticity and neurogenesis. Taken together, the GSK3b and CDK5 signaling pathways are important regulators of neurotoxicity in HIV, and modulation of these factors might have therapeutic potential in the treatment of patients suffering from HIVE. In this context, the subsequent sections will focus on reviewing the involvement of the GSK3b and CDK5 pathways in neurodegeneration in HIV. Full article

(This article belongs to the Special Issue Advances in Molecular Neuropathology)

► Show Figures

67 KiB

Open AccessArticle

Quantitative Prediction of Solvation Free Energy in Octanol of Organic Compounds

by Eduardo J. Delgado and Gonzalo A. Jaña

Int. J. Mol. Sci. 2009, 10(3), 1031-1044; https://doi.org/10.3390/i10031031 - 11 Mar 2009

Cited by 7 | Viewed by 11752

Abstract

The free energy of solvation, ΔG_S⁰ , in octanol of organic compunds is quantitatively predicted from the molecular structure. The model, involving only three molecular descriptors, is obtained by multiple linear regression analysis from a data set of 147 compounds [...] Read more.

The free energy of solvation, ΔG_S⁰ , in octanol of organic compunds is quantitatively predicted from the molecular structure. The model, involving only three molecular descriptors, is obtained by multiple linear regression analysis from a data set of 147 compounds containing diverse organic functions, namely, halogenated and non-halogenated alkanes, alkenes, alkynes, aromatics, alcohols, aldehydes, ketones, amines, ethers and esters; covering a ΔG_S⁰ range from about –50 to 0 kJ·mol-1. The model predicts the free energy of solvation with a squared correlation coefficient of 0.93 and a standard deviation, 2.4 kJ·mol-1, just marginally larger than the generally accepted value of experimental uncertainty. The involved molecular descriptors have definite physical meaning corresponding to the different intermolecular interactions occurring in the bulk liquid phase. The model is validated with an external set of 36 compounds not included in the training set. Full article

(This article belongs to the Special Issue Recent Advances in QSAR/QSPR Theory)

► Show Figures

Graphical abstract

1699 KiB

Open AccessArticle

Probing the Nanosecond Dynamics of a Designed Three-Stranded Beta-Sheet with a Massively Parallel Molecular Dynamics Simulation

by Vincent A. Voelz, Edgar Luttmann, Gregory R. Bowman and Vijay S. Pande

Int. J. Mol. Sci. 2009, 10(3), 1013-1030; https://doi.org/10.3390/ijms10031013 - 10 Mar 2009

Cited by 6 | Viewed by 13497

Abstract

Recently a temperature-jump FTIR study of a designed three-stranded sheet showing a fast relaxation time of ~140 ± 20 ns was published. We performed massively parallel molecular dynamics simulations in explicit solvent to probe the structural events involved in this relaxation. While our [...] Read more.

Recently a temperature-jump FTIR study of a designed three-stranded sheet showing a fast relaxation time of ~140 ± 20 ns was published. We performed massively parallel molecular dynamics simulations in explicit solvent to probe the structural events involved in this relaxation. While our simulations produce similar relaxation rates, the structural ensemble is broad. We observe the formation of turn structure, but only very weak interaction in the strand regions, which is consistent with the lack of strong backbone-backbone NOEs in previous structural NMR studies. These results suggest that either ^DP^DP-II folds at time scales longer than 240 ns, or that ^DP^DP-II is not a well-defined three-stranded β-sheet. This work also provides an opportunity to compare the performance of several popular forcefield models against one another. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

Graphical abstract

1515 KiB

Open AccessReview

Neuropathology and Therapeutic Intervention in Spinal and Bulbar Muscular Atrophy

by Haruhiko Banno, Masahisa Katsuno, Keisuke Suzuki, Fumiaki Tanaka and Gen Sobue

Int. J. Mol. Sci. 2009, 10(3), 1000-1012; https://doi.org/10.3390/ijms10031000 - 10 Mar 2009

Cited by 5 | Viewed by 12605

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The histopathological finding in SBMA is loss of lower motor neurons in the anterior horn of the spinal [...] Read more.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The histopathological finding in SBMA is loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic AR. Heat shock proteins, ubiquitin-proteasome system and transcriptional regulation are also potential targets of therapy development for SBMA. Full article

(This article belongs to the Special Issue Advances in Molecular Neuropathology)

► Show Figures

410 KiB

Open AccessArticle

Molecular Pathology of Human Prion Diseases

by Gabor G. Kovacs and Herbert Budka

Int. J. Mol. Sci. 2009, 10(3), 976-999; https://doi.org/10.3390/ijms10030976 - 9 Mar 2009

Cited by 69 | Viewed by 19803

Abstract

Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP) to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms [...] Read more.

Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP) to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis. Full article

(This article belongs to the Special Issue Advances in Molecular Neuropathology)

► Show Figures

Graphical abstract

270 KiB

Open AccessArticle

Kinetics of Chromium(III) Transport Through a Liquid Membrane Containing DNNSA as a Carrier

by Paweł Religa, Roman Gawroński and Paweł Gierycz

Int. J. Mol. Sci. 2009, 10(3), 964-975; https://doi.org/10.3390/ijms10030964 - 9 Mar 2009

Cited by 16 | Viewed by 10304

Abstract

Kinetics of Cr(III) ions transport through a bulk liquid membrane containing dinonylnaphthalenesulfonic acid (DNNSA) as a carrier, flowing over aqueous phases, has been examined. Special attention has been paid to the effect of the membrane’s velocity flow on the chromium concentration decrease in [...] Read more.

Kinetics of Cr(III) ions transport through a bulk liquid membrane containing dinonylnaphthalenesulfonic acid (DNNSA) as a carrier, flowing over aqueous phases, has been examined. Special attention has been paid to the effect of the membrane’s velocity flow on the chromium concentration decrease in a feed phase. For the description of relationships of chromium(III) concentration in particular phases with the time, a model based on the assumption of consecutive first-order reactions was proposed. Satisfactory compatibility of experiments and model results have been obtained both for the membrane flow velocities below 0.0034 m·s^-1 when the interfaces begin to fluctuate slightly and for low initial Cr(III) concentration in the feed phase. Full article

(This article belongs to the Section Green Chemistry)

► Show Figures

234 KiB

Open AccessArticle

Improvement of Morphine-Mediated Analgesia by Inhibition of β-Arrestin 2 Expression in Mice Periaqueductal Gray Matter

by Yuting Li, Xing Liu, Chang Liu, Jiuhong Kang, Jingyu Yang, Gang Pei and Chunfu Wu

Int. J. Mol. Sci. 2009, 10(3), 954-963; https://doi.org/10.3390/ijms10030954 - 5 Mar 2009

Cited by 50 | Viewed by 15658

Abstract

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly [...] Read more.

Morphine is a well-known μ-opioid receptor (MOR) agonist and an efficient analgesic, but its long-term use inevitably leads to drug addiction and tolerance. Here, we show that specific inhibition of β-arrestin2 with its siRNA lentivirus microinjected in mice periaqueductal gray matter (PAG) significantly improved both acute and chronic morphine analgesia and delayed the tolerance in the hotplate test. The specific effect of β-arrestin2 was proven by overexpression or knockdown of its homology β-arrestin1 in PAG, which showed no significant effects on morphine analgesia. These findings suggest that specific siRNA targeting β-arrestin2 may constitute a new approach to morphine therapy and other MOR agonist-mediated analgesia and tolerance. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

Graphical abstract

122 KiB

Open AccessArticle

The Contribution of the Elastic Reaction is Severely Underestimated in Studies on Myofibril Contraction

by Enrico Grazi and Sara Pozzati

Int. J. Mol. Sci. 2009, 10(3), 942-953; https://doi.org/10.3390/ijms10030942 - 2 Mar 2009

Cited by 2 | Viewed by 10387

Abstract

We have considered the Huxley-Simmons manoeuvre. On the assumption that the quick release is an elastic process and on the basis of the isometric tension and of the stiffness of the muscle fibre we calculated that the spontaneous release of the fibre requires [...] Read more.

We have considered the Huxley-Simmons manoeuvre. On the assumption that the quick release is an elastic process and on the basis of the isometric tension and of the stiffness of the muscle fibre we calculated that the spontaneous release of the fibre requires ~43 μs, which is much faster than the observed release, ~180 μs. We concluded that the observed quick release is a guided process. After proper selection of the mass and of the stiffness of the system we mimicked the early recovery and noticed that most of the energy required to accomplish the early recovery is supplied by the kinetic energy accumulated during the course of the quick release. We computed that the frequency of the working strokes in the half sarcomere was between 4×10⁶ and 40×10⁶ s^-1. This is not to say that the ATPase rate constants are accumulative but only that the overall frequency of the working strokes in the half saromere is many orders of magnitude faster than the average ATPase rate constant. With this frequency no part of the Huxley-Simmons manoeuvre, quick release included, escapes the control of the working stroke. This means also that there is no reason to take the early recovery as an indication of the length of the working stroke. Full article

► Show Figures

196 KiB

Open AccessArticle

Corrrelation of the Specific Rates of Solvolysis of Ethyl Fluoroformate Using the Extended Grunwald-Winstein Equation

by Mi Hye Seong, Jin Burm Kyong, Young Hoon Lee and Dennis N. Kevill

Int. J. Mol. Sci. 2009, 10(3), 929-941; https://doi.org/10.3390/ijms10030929 - 2 Mar 2009

Cited by 5 | Viewed by 12318

Abstract

The specific rates of solvolysis of ethyl fluoroformate have been measured at 24.2 °C in 21 pure and binary solvents. These give a satisfactory correlation over the full range of solvents when the extended Grunwald-Winstein equation is applied. The sensitivities to changes in [...] Read more.

The specific rates of solvolysis of ethyl fluoroformate have been measured at 24.2 °C in 21 pure and binary solvents. These give a satisfactory correlation over the full range of solvents when the extended Grunwald-Winstein equation is applied. The sensitivities to changes in the N_T solvent nucleophilicity scale and the Y_Cl solvent ionizing power scale, and the k_F/k_Clvalues are very similar to those for solvolyses of n-octyl fluoroformate, consistent with the addition step of an addition-elimination pathway being rate-determining. For methanolysis, a solvent deuterium isotope effect of 3.10 is compatible with the incorporation of general-base catalysis into the substitution process. For five representative solvents, studies were made at several temperatures and activation parameters determined. The results are also compared with those reported earlier for ethyl chloroformate and mechanistic conclusions are drawn. Full article

(This article belongs to the Special Issue Grunwald-Winstein Equations – 60 Years & Counting)

► Show Figures

Graphical abstract

939 KiB

Open AccessReview

Multiple, but Concerted Cellular Activities of the Human Protein Hap46/BAG-1M and Isoforms

by Ulrich Gehring

Int. J. Mol. Sci. 2009, 10(3), 906-928; https://doi.org/10.3390/ijms10030906 - 2 Mar 2009

Cited by 9 | Viewed by 16190

Abstract

The closely related human and murine proteins Hap46/BAG-1M and BAG-1, respectively, were discovered more than a decade ago by molecular cloning techniques. These and the larger isoform Hap50/BAG-1L, as well as shorter isoforms, have the ability to interact with a seemingly unlimited array [...] Read more.

The closely related human and murine proteins Hap46/BAG-1M and BAG-1, respectively, were discovered more than a decade ago by molecular cloning techniques. These and the larger isoform Hap50/BAG-1L, as well as shorter isoforms, have the ability to interact with a seemingly unlimited array of proteins of completely unrelated structures. This problem was partially resolved when it was realized that molecular chaperones of the hsp70 heat shock protein family are major primary association partners, binding being mediated by the carboxy terminal BAG-domain and the ATP-binding domain of hsp70 chaperones. The latter, in turn, can associate with an almost unlimited variety of proteins through their substrate-binding domains, so that ternary complexes may result. The protein folding activity of hsp70 chaperones is affected by interactions with Hap46/BAG-1M or isoforms. However, there also exist several proteins which bind to Hap46/BAG-1M and isoforms independent of hsp70 mediation. Moreover, Hap46/BAG-1M and Hap50/BAG-1L, but not the shorter isoforms, can bind to DNA in a sequence-independent manner by making use of positively charged regions close to their amino terminal ends. This is the molecular basis for their effects on transcription which are of major physiological relevance, as discussed here in terms of a model. The related proteins Hap50/BAG-1L and Hap46/BAG-1M may thus serve as molecular links between such diverse bioactivities as regulation of gene expression and protein quality control. These activities are coordinated and synergize in helping cells to cope with conditions of external stress. Moreover, they recently became markers for the aggressiveness of several cancer types. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

470 KiB

Open AccessReview

Insights from Coarse-Grained Gō Models for Protein Folding and Dynamics

by Ronald D. Hills, Jr. and Charles L. Brooks III

Int. J. Mol. Sci. 2009, 10(3), 889-905; https://doi.org/10.3390/ijms10030889 - 2 Mar 2009

Cited by 213 | Viewed by 19168

Abstract

Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō [...] Read more.

Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō models, which constitute a smooth and funnel-like approximation to the folding landscape. We review the many variations of the Gō model that have been employed to yield insight into folding mechanisms. Their success has been interpreted as a consequence of the dominant role of the native topology in folding. The role of local contact density in determining protein dynamics is also discussed and is used to explain the ability of Gō-like models to capture sequence effects in folding and elucidate conformational transitions. Full article

(This article belongs to the Special Issue Protein Folding 2009)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 10, Issue 3 (March 2009) – 39 articles , Pages 724-1418

Further Information

Guidelines

MDPI Initiatives

Follow MDPI