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  • 1
    Keywords: DENSITY-FUNCTIONAL-THEORY ; DFT ; INFORMATION ; NEW-YORK ; MOLECULES ; MOLECULE ; NO ; RELIABILITY ; EXPLICIT WATER-MOLECULES ; ROTATIONAL STRENGTHS ; CHAIN ; RE ; ALANYL-L-ALANINE ; DIPOLE TRANSITION MOMENTS ; VIBRATIONAL CIRCULAR-DICHROISM ; conformational analysis ; LEVEL ; analysis ; USA ; AQUEOUS-SOLUTION ; VA ; Aframodial ; ATOMIC POLAR ; AXIAL TENSORS ; B3LYP ; OPTICALLY-ACTIVE MOLECULES ; PBE ; VCD ; vibrational spectroscopy
    Abstract: In this work we present the experimental and theoretical vibrational absorption (VA) and the theoretical vibrational circular dichroism (VCD) spectra for aframodial. In addition, we present the theoretical VA and VCD spectra for the diasteriomers of aframodial. Aframodial has four chiral centers and hence has 2(4) = 16 diasteriomers, which occur in eight pairs of enantiomers. In addition to the four chiral centers, there is an additional chirality due to the helicity of the entire molecule, which we show by presenting 12 configurations of the 5S,8S,9R,10S enantiomer of aframodial. The VCD spectra for the diasteriomers and the 12 configurations of one enantiomer are shown to be very sensitive not only to the local stereochemistry at each chiral center, but in addition, to the helicity of the entire molecule. Here one must be careful in analyzing the signs of the VCD bands due to the 'non-chiral' chromophores in the molecule, since one has two contributions; one due to the inherent chirality at the four chiral centers, and one due to the chirality of the side chain groups in specific conformers, that is, its helicity. Theoretical simulations for various levels of theory are compared to the experimental VA recorded to date. The VCD spectra simulations are presented, but no experimental VCD and Raman spectra have been reported to date, though some preliminary VCD measurements have been made in Stephens' lab in Los Angeles. The flexible side chain is proposed to be responsible for the small size of the VCD spectra of this molecule, even though the chiral part of the molecule is very rigid and has four chiral centers. In addition to VCD and Raman measurements, Raman optical activity (ROA) measurements would be very enlightening, as in many cases bands which are weak in both the VA and VCD, may be large in the Raman and/or ROA spectra. The feasibility of using vibrational spectroscopy to monitor biological structure, function and activity is a worthy goal, but this work shows that a careful theoretical analysis is also required, if one is to fully utilize and understand the experimental results. The reliability, reproduceability and uniqueness of the vibrational spectroscopic experiments and the information which can be gained from them is discussed, as well as the details of the computation of VA, VCD and Raman (and ROA) spectroscopy for molecules of the complexity of aframodial, which have multiple chiral centers and flexible side chains
    Type of Publication: Journal article published
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  • 2
    Abstract: Coarse-grained models are used to assess the packing of the 30-nm chromatin fiber. First, rigid assembly models for nucleosomal repeats from 155 to 211 bp are built using the crystal structure of the mononucleosome and attached straight stretches of B-DNA. The resulting fiber conformations are analyzed for static clashes and classified into stable and unstable structures. The effect of flexibility and thermal fluctuations is then taken into account by conducting Monte Carlo simulations of chromatin fiber models. Here the DNA is approximated by a flexible polymer chain with Debye-Huckel electrostatics, the geometry of the linker DNA connecting the nucleosomes is based on a two-angle zigzag model, and nucleosomes are represented by flat ellipsoids interacting via an attractive Gay-Berne potential. Unstable fibers occur at a particular repeat length period of 10 bp. Also, the regions of densely compacted fibers repeat at intervals of 10 bp. Besides one- and two-start helical zigzag structures, we show evidence for possible three-start structures, which have not been reported in experiments yet. Finally, we show that a local opening of the linker DNA at the nucleosome core-as probably occurs upon histone acetylation-leads to more open and flexible structures.
    Type of Publication: Journal article published
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  • 3
    Keywords: INFORMATION ; PROTEINS ; MOLECULES ; ENERGY ; DENSITY-FUNCTIONAL THEORY ; RAMAN OPTICAL-ACTIVITY ; VIBRATIONAL CIRCULAR-DICHROISM ; Raman optical activity ; vibrational circular dichroism ; Genetic ; molecular biophysics ; Quantum chemistry ; CONFIGURATION-INTERACTION CALCULATIONS ; CYTOSINE BASE PAIR ; GROUND-STATE CHARACTERIZATION ; LES ETATS ELECTRONIQUES ; LOWER EXCITED SINGLET ; Nucleic acids ; Photosynthesis ; PHOTOSYNTHETIC REACTION-CENTER ; PRIMARY CHARGE SEPARATION ; Quantum nanobiology ; Quinones
    Abstract: We discuss how the basic principles of quantum chemistry and quantum mechanics can be and have been applied to a variety of problems in molecular biophysics. First, the historical development of quantum concepts in biophysics is discussed. Next, we describe a series of interesting applications of quantum chemical methods for studying biologically active molecules, molecular structures, and some of the important processes which play a role in living organisms. We discuss the application of quantum chemistry to such processes as energy storage and transformation, and the transmission of genetic information. Quantum chemical approaches are essential to comprehend and understand the molecular nature of these processes. To conclude our work, we present a short discussion of the perspectives of quantum chemical methods in modern biophysics, the field of experimental and theoretical chiral vibrational and electronic spectroscopy
    Type of Publication: Journal article published
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  • 4
    Keywords: CELLS ; EXPRESSION ; Germany ; MODEL ; INFORMATION ; SYSTEM ; DISEASE ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; microarray ; TISSUE ; DISCOVERY ; TARGET ; IDENTIFICATION ; PATTERNS ; DNA microarray ; DESIGN ; DATABASE ; TARGETS ; DIFFERENTIAL EXPRESSION ; EXPRESSED SEQUENCE TAGS ; biomarker ; THERAPEUTIC TARGETS ; EST ; KNOWLEDGEBASE ; TIGR GENE INDEXES ; Tissue ontology ; Tissue slims ; Tissue synonym library ; Tissue type ; Tissue-distribution pattern ; Tissue-distribution profiles
    Abstract: Tissue-distribution profiles are crucial for understanding the characteristics of cells and tissues in terms of their differential expression of genes. Most of the currently available resources for tissue-distribution profiles are either specialized for a few particular organisms, tissue types and disease stages or do not consider the "tissue ontology" levels for the calculation of the tissue-distribution profiles. Therefore, we have developed "TissueDistributionDBs", a repository of tissue-distribution profiles based on the expressed sequence tags (ESTs) data extracted from the UniGene database by employing "Tissue Ontology" available at BRENDA. To overcome the occurrence of the natural language variations in the EST's source tissue-type terms, we have generated a "tissue synonym library" and standardized these tissue-type terms by cross-referencing to the controlled vocabulary for tissue-type terms available at BRENDA "Tissue Ontology". Furthermore, we have provided a quantitative expression for genes among the tissue types at various anatomical levels by constructing "tissue slims". Concurrently, the expression among tissue types is used for tissue-distribution calculations. The resulting output profiles can be queried by the Sequence Retrieval System (SRS) and are currently available for 20 different model organisms. We benchmarked our database system against the Swissprot database using a set of 40 different tissue types. This database system is useful for the understanding of the tissue-specific expression patterns of genes, which have implications for the identification of possible new therapeutic drug targets, in gene discovery, and in the design and analysis of micro-arrays. TissueDistributionDBs can be accessed via the World Wide Web (www) at "http://genius.embnet.dkfz-heidelberg.de/menu/tissue_db/"
    Type of Publication: Journal article published
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  • 5
    Keywords: MECHANISM ; WATER ; COLLISION-INDUCED DISSOCIATION ; SPECTROMETRY ; PEPTIDES ; AMIDE BOND ; TANDEM MASS-SPECTRA ; ALPHA-AMINO-ACIDS ; ENERGY CORRELATIONS ; TRIPEPTIDES
    Abstract: The fragmentation chemistry of protonated H-Val-Asn-OH, H-Val-Gln-OH and H-Val-Lys-OH is investigated in this work by means of modeling and density functional theory calculations. Former experimental studies indicate that the ratio of a (1) and y (1) ions cannot be explained by considering the proton affinities of the corresponding dissociating species on the a (1)-y (1) pathway, while the fragmentation of other dipeptides can be understood in this way. We demonstrate that considering the correct PA value for H-Asn-OH eliminates the deviation observed for H-Val-Asn-OH. The larger than expected a (1)/y (1) ratio of H-Val-Gln-OH is explained by considering the dissociation kinetics of the proton-bound dimers formed on the a (1)-y (1) pathway and competition of the deamidation and a (1)-y (1) channels. For H-Val-Lys-OH, it is proposed that a (1) ions are indeed formed from one of the primary products, protonated H-Val-Cap-OH.
    Type of Publication: Journal article published
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  • 6
    Keywords: CANCER ; CELLS ; MODEL ; MOLECULES ; SPECTROSCOPY ; Raman ; ABSORPTION ; principal component analysis ; VIBRATIONAL CIRCULAR-DICHROISM ; cluster analysis ; statistical methods ; NEURAL-NETWORKS ; Colorectal cancer diagnosis ; CONTINUUM SOLVATION MODELS ; DENSITY-FUNCTIONAL ANALYSIS ; ELONGATION METHOD ; First principles ; Image generation ; Infrared ; Infrared imaging ; IR MICROSPECTROSCOPY ; L-ALANINE ; Linear discriminant analysis ; Molecular mechanics ; Raman imaging
    Abstract: In this work, we present the state of the art in the use of theory (first principles, molecular dynamics, and statistical methods) for interpreting and understanding the infrared (vibrational) absorption and Raman scattering spectra. It is discussed how they can be used in combination with purely experimental studies to generate infrared and Raman images of biomolecules in biologically relevant solutions, including fluids, cells, and both healthy and diseased tissue. The species and conformers of the individual biomolecules are in many cases not stable structures, species, or conformers in the isolated state or in non-polar non-strongly interacting solvents. Hence, it is better to think of the collective behavior of the system. The collective interaction is not the simple sum of the individual parts. Here, we will show that this is also not true for the infrared and Raman spectra and images and that the models used must take this into account. Hence, the use of statistical methods to interpret and understand the infrared and Raman spectra and images from biological tissues, cells, parts of cells, fluids, and even whole organism should change accordingly. As the species, conformers and structures of biomolecules are very sensitive to their environment and aggregation state, the combined use of infrared and Raman spectroscopy and imaging and theoretical simulations are clearly fields, which can benefit from their joint and mutual development
    Type of Publication: Journal article published
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  • 7
    Keywords: COMBINATION ; Germany ; ALGORITHM ; TOOL ; GENE ; MOTIFS ; TRANSCRIPTION FACTOR ; BINDING ; SEQUENCES ; DISCOVERY ; IDENTIFICATION ; PROMOTER ; DATABASE ; REGION ; INTERFACE ; PREDICTION ; W2H ; FRAMEWORK ; ANNOTATION ; Motif discovery
    Abstract: There are many tools available for the prediction of potential promoter regions and the transcription factor binding sites (TFBS) harboured by them. Unfortunately, these tools cannot really avoid the prediction of vast amounts of false positives, the greatest problem in promoter analysis. The combination of different methods and algorithms has shown an improvement in prediction accuracy for similar biological problems such as gene prediction. The web-tool presented here uses this approach to perform an exhaustive integrative analysis, identification and annotation of potential promoter regions. The combination of methods employed includes searches in different experimental promoter databases to identify promoter regions and their orthologs, use of TFBS databases and search tools, and a phylogenetic footprinting strategy, combining multiple alignment of genomic sequences together with motif discovery tools that were tested previously in order to get the best method combination. The pipeline is available for academic users at the HUSAR open server "http://genius.embnet.dkfz-heidelberg.de/menu/biounit/open-husar/" . It integrates all of this information and identifies among the huge number of TFBS predictions those, which are more likely to be potentially functional
    Type of Publication: Journal article published
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  • 8
    Keywords: DENSITY-FUNCTIONAL-THEORY ; DFT ; SCC-DFTB ; EXPRESSION ; Germany ; SYSTEM ; SYSTEMS ; BINDING ; ENERGY ; TIGHT-BINDING METHOD ; proton transfer ; QM/MM ; density functional theory ; excited states ; CONFIGURATION-INTERACTION PROCEDURE ; EXPANSION ; ADAPTED PERTURBATION-THEORY ; dispersion interaction ; hydrogen bonds ; LONG-RANGE BEHAVIOR ; POST-HARTREE-FOCK ; RARE-GAS DIATOMICS ; REACTION-PATH DYNAMICS ; SCC-DFTB METHOD ; TD-DFT ; TRANSFER EXCITED-STATES ; VAN-DER-WAALS
    Abstract: The Self-consistent charge density functional tight-binding (SCC-DFTB) is an approximate quantum chemical method derived from density functional theory (DFT) based on a second-order expansion of the DFT total energy expression. Here, we review in detail the application of SCC-DFTB to biological systems and several extensions of the original formalism. The biological systems discussed turn out to be a challenge for DFT due to the occurrence of weak binding forces and charge transfer problems, both of which are not properly described by recent DFT-GGA functionals. Possible solutions and alternative strategies are presented and the role of SCC-DFTB in a general quantum chemical approach to biological systems is discussed
    Type of Publication: Journal article published
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  • 9
    Keywords: AB-INITIO ; DNA ; BINDING ; GAS-PHASE ; MOLECULAR-DYNAMICS ; GENERALIZED GRADIENT APPROXIMATION ; Adenine-thymine base pairs ; Anharmonic corrections ; BASIS-SETS ; BSSE effect ; DENSITY-FUNCTIONAL COMPUTATIONS ; DYNAMIC ELECTRON CORRELATION ; H-stretching vibration ; HARMONIC APPROXIMATION ; MP2 CALCULATIONS ; PLESSET PERTURBATION-THEORY ; Urea dimer
    Abstract: The equilibrium structures, binding energies, vibrational harmonic frequencies, and the anharmonic corrections for two different (cyclic and asymmetric) urea dimers and for the adenine-thymine DNA base pair system have been studied using the second-order Moller-Plesset perturbation theory (MP2) method and different density functional theory (DFT) exchange-correlation (XC) functionals (BLYP, B3LYP, PBE, HCTH407, KMLYP, and BH and HLYP) with the D95V, D95V**, and D95V++** basis sets. The widely used a posteriori Boys-Bernardi or counterpoise correction scheme for basis set superposition error (BSSE) has been included in the calculations to take into account the BSSE effects during geometry optimization (on structure), on binding energies and on the different levels of approximation used for calculating the vibrational frequencies. The results obtained with the ab initio MP2 method are compared with those calculated with different DFT XC functionals; and finally the suitability of these DFT XC functionals to describe intermolecular hydrogen bonds as well as harmonic frequencies and the anharmonic corrections is assessed and discussed
    Type of Publication: Journal article published
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  • 10
    Keywords: RECEPTOR ; CANCER ; Germany ; MOLECULES ; COMPLEX ; DNA ; BINDING ; ENERGY ; vibrational absorption ; ESTROGEN-RECEPTOR ; estrogen receptor ; vibrational circular dichroism ; Anti-cancer drug ; Charged Ru complex ; Competitive binding
    Abstract: Following up on an earlier theoretical report by Knapp-Mohammady (Phys Lett A 372:1881-1884, 2008) on the ground state of the neutral Ru complex NAMI-A (trans-imidazoledimethylsulfoxide-tetrachlororuthenate), we first report here a quantum-chemical study of the effect of both oxidation and reduction of the parent molecule to form the anionic and cationic species. The new structures are compared with the equilibrium nuclear structure reported earlier for the neutral complex. We anticipate that one such Ru cluster, with potential as an anti-cancer drug, will interact via an appropriate receptor, rather than directly with DNA. A receptor for NAMI-A binding in here proposed to be the steroid hormone, estrogen, C18H24O2. The biomolecular structure of the dicomplex is predicted from restricted Hartree-Fock theory and density functional theory (DFT) calculations. The vibrational frequencies of NAMI-A and the dicomplex with estrogen are also reported. Some maps of the ground-state electron-density for the three neutral biomolecular species are finally presented. The use of vibrational spectroscopy, vibrational absorption (VA) and vibrational circular dichorism (VCD) are advocated to be measured, simulated and be used to understand the nature of the interaction of the Ru complex NAMI-A in complex with estrogen. Our aim in presenting these spectral simulations is to motivate the measurement of the VA and VCD spectra of estrogen, the Ru complex NAMI-A and finally of the estrogen-Ru NAMI-A complex. It should also be instructive to measure the VA and VCD spectra of estrogen and the estrogen receptor, both alone, together and finally together in the presence of the Ru NAMI-A complex to substantiate our claim that the Ru complex NAMI-A ties up estrogen, and hence prevents estrogen binding to the estrogen receptor
    Type of Publication: Journal article published
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