Computational modelling and optimization studies of electropentamer for molecular imprinting of DJ-1.

Parkinson's disease (PD) is the most prevalent type of incurable movement disorder. Recent research findings propose that the familial PD-associated molecule DJ-1 exists in cerebrospinal fluid (CSF) and that its levels may be altered as Parkinson's disease advances. By using a molecularly imprinted polymer (MIP) as an artificial receptor, it becomes possible to create a functional MIP with predetermined selectivity for various templates, particularly for the DJ-1 biomarker associated with Parkinson's disease. It mostly depends on molecular recognition via interactions between functional monomers and template molecules. So, the computational methods for the appropriate choice of functional monomers for creating molecular imprinting electropolymers (MIEPs) with particular recognition for the detection of DJ-1, a pivotal biomarker involved in PD, are undertaken in this study. Here, molecular docking, molecular dynamics simulations (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods, and quantum mechanical calculation have been applied to investigate the intermolecular interaction between DJ-1 and several functional electropentamers, viz., polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT), poly(o-aminophenol) (POAP), and polythiophene (PTS). In this context, the electropentamers were selected to mimic the imprinted electropolymer system. We analyzed the most stable configurations of the formed complexes involving DJ-1 and electropentamers as a model system for MIEPs. Among these, PEDOT exhibited a more uniform arrangement around DJ-1, engaging in numerous van der Waals, H-bond, electrostatic, and hydrophobic interactions. Hence, it can be regarded as a preferable choice for synthesizing a MIP for DJ-1 recognition. Thus, it will aid in selecting a suitable functional monomer, which is of greater significance in the design and development of selective DJ-1/MIP sensors.

Dynamics and fragmentation mechanism of (C5H4CH3)Pt(CH3)3 on SiO2 surfaces.

The interaction of trimethyl(methylcyclopentadienyl)platinum(IV) ((C5H4CH3)Pt(CH3)3) molecules on fully and partially hydroxylated SiO2 surfaces, as well as the dynamics of this interaction were investigated using density functional theory (DFT) and finite temperature DFT-based molecular dynamics simulations. Fully and partially hydroxylated surfaces represent substrates before and after electron beam treatment and this study examines the role of electron beam pretreatment on the substrates in the initial stages of precursor dissociation and formation of Pt deposits. Our simulations show that on fully hydroxylated surfaces or untreated surfaces, the precursor molecules remain inactivated while we observe fragmentation of (C5H4CH3)Pt(CH3)3 on partially hydroxylated surfaces. The behavior of precursor molecules on the partially hydroxylated surfaces has been found to depend on the initial orientation of the molecule and the distribution of surface active sites. Based on the observations from the simulations and available experiments, we discuss possible dissociation channels of the precursor.

Temperature-dependent conformational dynamics of cytochrome c: Implications in apoptosis.

Heat, electric shock, and burn injuries induce apoptosis by releasing cytochrome c (cyt-c) from mitochondria and by subsequently activating the death protease, caspases-3. During apoptosis, cyt-c undergoes changes in the secondary structure that have been suggested to increase its peroxidase activity. Information about these structural changes will provide better understanding of the apoptotic mechanism. Hence, temperature-dependent conformational dynamics of cyt-c has been investigated through molecular dynamics (MD) simulations to explain the structural changes and to correlate them with its apoptotic behavior. We observe that, at lower temperatures (223, 248, and 300K), the secondary structure of cyt-c, remains stable, while at higher temperatures (323, 373, 423, and 473K), the secondary structural regions change significantly. Further, our MD results indicate that these structural changes are mainly localized on α-helices, turns, ß-sheets, and important loops that were involved in the stabilization of the heme conformation. This conformational transition between specific regions of secondary structure of cyt-c directly affects the electron tunneling properties of the proteins as observed experimentally. We quantify and compare these changes and explain that the temperature plays a vital role in assuring the structural stability of cyt-c and thus its functions. Our findings from this MD study reproduce experimental results at high temperatures and provide evidence for the alteration of the heme through the disruption of the H-bonding interactions between specific regions of cyt-c, thereby enhancing its peroxidase activity which plays a crucial role in the apoptotic process.

Investigation of structural dynamics of Thrombocytopenia Cargeeg mutants of human apoptotic cytochrome c: A molecular dynamics simulation approach.

Naturally occurring mutations to cytochrome c (cyt-c) have been identified recently in patients with mild autosomal dominant thrombocytopenia (low platelet levels), which yield cyt-c mutants with enhanced apoptotic activity. However, the molecular mechanism underlying this low platelet production and enhanced apoptosis remain unclear. Therefore, an attempt is made herein for the first time to investigate the effects of mutations of glycine 41 by serine (G41S) and tyrosine 48 by histidine (Y48H) on the conformational and dynamic changes of apoptotic (Fe3+) cyt-c using all atom molecular dynamics (MD) simulations in explicit water solvent. Our 30ns MD simulations demonstrate considerable structural differences in G41S and Y48H compared to wild type (WT) cyt-c, such as increasing distances between the critical electron transfer residues results in open conformation at the heme active site, large fluctuations in ß-turns and α-helices. Additionally, although the ß-sheets remain mostly unaffected in all the three cyt-c simulations, the α-helices undergo conformational switch to ß-turns in both the mutant simulations. Importantly, this conformational switch of α-helix to ß-turn around heme active site should attributes to the loss of intraprotein H-bonds in the mutant simulations especially between NE2 (His26) and O (Pro44) in agreement with the experimental report. Further, essential dynamics analysis reveals that overall motions of WT cyt-c is mainly involved only in the first eigenvector, but in G41S and Y48H the overall motions are mainly in three and two eigenvectors respectively. Overall, the detailed atomistic level information provide a unifying description for the molecular mechanism of structural destabilization, disregulation of platelet formation and enhanced peroxidase activity of the mutant cyt-c's in the pathology of intrinsic apoptosis.

Effects of different solvents on the conformations of apoptotic cytochrome c: Structural insights from molecular dynamics simulation.

Cytochrome c (cyt-c) upon binding with cardiolipin acquires peroxidase activity and is strictly connected to the pathogenesis of many human diseases including neurodegenerative and cardiovascular diseases. Interaction of cyt-c with cardiolipin mimics partial unfolding/conformational changes of cyt-c in different solvent environments. Dynamic pictures of these conformational changes of cyt-c are crucial in understanding their physiological roles in mitochondrial functions. Therefore, atomistic molecular dynamics (MD) simulations have been carried out to investigate the effect of different solvents (water, urea/water, MeOH and DMSO) on the structure and conformations of apoptotic cyt-c (Fe3+). Our study demonstrates that the structural changes in the protein are solvent dependent. The structural differences are observed majorly on the ß-sheets and α-helical conformations and the degree of their perturbation are specific to the solvent. Although a complete loss of ß-sheets (0%) is observed in MeOH and DMSO, by contrast, well preserved ß-sheets (3.84%) are observed in water and urea/water. A significant decrease in the α-helical contents is observed in MeOH (41.34%) and water (42.46%), a negligible alteration in DMSO (44.25%) and well preserved α-helical (45.19%) contents in urea/water. The distances between the residues critical for electron transfer are decreased considerably for DMSO. Further, the reduction in residue flexibility and the conformational space indicate that the collective motions of cyt-c are reduced when compared to other cosolvents. Essential dynamics analysis implies that the overall motions of cyt-c in water, MeOH and urea/water are involved in three to four eigenvectors and in first eigenvector in DMSO. Overall, we believe that MD simulations of cyt-c in different solvents can provide a detailed microscopic understanding of the physiological roles, electron transport and peroxidase function in the early events of apoptosis which are hard to probe experiments.

Dynamics of tungsten hexacarbonyl, dicobalt octacarbonyl, and their fragments adsorbed on silica surfaces.

Tungsten and cobalt carbonyls adsorbed on a substrate are typical starting points for the electron beam induced deposition of tungsten or cobalt based metallic nanostructures. We employ first principles molecular dynamics simulations to investigate the dynamics and vibrational spectra of W(CO)6 and W(CO)5 as well as Co2(CO)8 and Co(CO)4 precursor molecules on fully and partially hydroxylated silica surfaces. Such surfaces resemble the initial conditions of electron beam induced growth processes. We find that both W(CO)6 and Co2(CO)8 are stable at room temperature and mobile on a silica surface saturated with hydroxyl groups (OH), moving up to half an Angström per picosecond. In contrast, chemisorbed W(CO)5 or Co(CO)4 ions at room temperature do not change their binding site. These results contribute to gaining fundamental insight into how the molecules behave in the simulated time window of 20 ps and our determined vibrational spectra of all species provide signatures for experimentally distinguishing the form in which precursors cover a substrate.

Giant pressure-induced volume collapse in the pyrite mineral MnS2.

Dramatic volume collapses under pressure are fundamental to geochemistry and of increasing importance to fields as diverse as hydrogen storage and high-temperature superconductivity. In transition metal materials, collapses are usually driven by so-called spin-state transitions, the interplay between the single-ion crystal field and the size of the magnetic moment. Here we show that the classical S = 5/2 mineral hauerite (MnS2) undergoes an unprecedented (ΔV ~ 22%) collapse driven by a conceptually different magnetic mechanism. Using synchrotron X-ray diffraction we show that cold compression induces the formation of a disordered intermediate. However, using an evolutionary algorithm we predict a new structure with edge-sharing chains. This is confirmed as the thermodynamic ground state using in situ laser heating. We show that magnetism is globally absent in the new phase, as low-spin quantum S = 1/2 moments are quenched by dimerization. Our results show how the emergence of metal-metal bonding can stabilize giant spin-lattice coupling in Earth's minerals.

Comparative structural and conformational studies on H43R and W32F mutants of copper-zinc superoxide dismutase by molecular dynamics simulation.

Recently, mutations in copper-zinc superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (fALS), a progressive neurodegenerative disease involving motor neuron loss, paralysis and death. It is mainly due to protein misfolding and aggregation resulting from the enhanced peroxidase activity of SOD1 mutants. In this study, we have carried out a 20 ns molecular dynamics simulation for wild type (WT), H43R and W32F mutated SOD1's dimer and compared their structure and conformational properties by extracting several quantitative properties from the trajectory to understand the pathology of fALS disease. Our results show considerable differences in H43R compared to WT and W32F mutated SOD1, such as increasing distances between the critical residues results in open conformation at the active site, strong fluctuations in the important loops (Zinc and electrostatic loops) and weakening of important hydrogen bonds especially between N (His 43/Arg 43) and carbonyl oxygen (His 120) in agreement with the experimental report. The calculated buried surface area of dimer interface for WT, H43R and W32F are 682, 726 and 657 Å(2) respectively, representing the loss of dimerization in H43R. Essential dynamics reveal that overall motions of WT and W32F are mainly involved in three to four eigenvectors, but in H43R the overall motions are mainly in the first eigenvector. These data thus provide a unifying description for the structural destabilization, enhanced peroxidase activity, loss of dismutation activity and increase in aggregation propensity in the pathology of fALS diseases.

Spontaneous dissociation of Co(2)(CO)(8) and autocatalytic growth of Co on SiO(2): A combined experimental and theoretical investigation.

We present experimental results and theoretical simulations of the adsorption behavior of the metal-organic precursor Co(2)(CO)(8) on SiO(2) surfaces after application of two different pretreatment steps, namely by air plasma cleaning or a focused electron beam pre-irradiation. We observe a spontaneous dissociation of the precursor molecules as well as autodeposition of cobalt on the pretreated SiO(2) surfaces. We also find that the differences in metal content and relative stability of these deposits depend on the pretreatment conditions of the substrate. Transport measurements of these deposits are also presented. We are led to assume that the degree of passivation of the SiO(2) surface by hydroxyl groups is an important controlling factor in the dissociation process. Our calculations of various slab settings, using dispersion-corrected density functional theory, support this assumption. We observe physisorption of the precursor molecule on a fully hydroxylated SiO(2) surface (untreated surface) and chemisorption on a partially hydroxylated SiO(2) surface (pretreated surface) with a spontaneous dissociation of the precursor molecule. In view of these calculations, we discuss the origin of this dissociation and the subsequent autocatalysis.

Theoretical investigation of quinone metabolites of dopamine interaction with DNA--insights into toxicological effects.

Dopamine (3,4-dihydroxyphenylethylamine, DA), an important neurotransmitter, exists in the cell bodies of the dopaminergic neurons of the substantia nigra. Oxidation of DA to its quinone and subsequent reaction with Adenine and Guanine in DNA result in the formation of depurinating adducts, thus causing DNA damage. In this article, we investigate the interaction of quinone metabolites of dopamine (DMQ) with models representing the structure of DNA using dispersion corrected density functional theory with an aim to evaluate the associated structural changes in DNA upon their interaction. Various binding sites for the DA metabolite on these DNA models have been considered and our computations on the activation barriers allowed us to identify preferential bonding sites for these metabolites analogous to experiments. Analysis of the geometry of these adducts in comparison to free base pairs reveals that the attack of DMQ causes remarkable changes in the structural properties. With our calculations, we propose that these structural alterations induce mutations by favoring the formation of depurinating adducts leading to mutagenic effects such as base mispairing, explaining the toxicological (carcinogenic and neurotoxic) behavior of DMQ.