Basis set and electron correlation effects on initial convergence for vibrational nonlinear optical properties of conjugated organic molecules

The level of ab initio theory which is necessary to compute reliable values for the static and dynamic (hyper)polarizabilities of three medium size π-conjugated organic nonlinear optical (NLO) molecules is investigated. With the employment of field-induced coordinates in combination with a finite field procedure, the calculations were made possible. It is stated that to obtain reasonable values for the various individual contributions to the (hyper)polarizability, it is necessary to include electron correlation. Based on the results, the convergence of the usual perturbation treatment for vibrational anharmonicity was examined

Intramolecular basis set superposition error effects on the planarity of benzene and other aromatic molecules: A solution to the problem

Recently, the surprising result that ab initio calculations on benzene and other planar arenes at correlated MP2, MP3, configuration interaction with singles and doubles (CISD), and coupled cluster with singles and doubles levels of theory using standard Pople’s basis sets yield nonplanar minima has been reported. The planar optimized structures turn out to be transition states presenting one or more large imaginary frequencies, whereas single-determinant-based methods lead to the expected planar minima and no imaginary frequencies. It has been suggested that such anomalous behavior can be originated by two-electron basis set incompleteness error. In this work, we show that the reported pitfalls can be interpreted in terms of intramolecular basis set superposition error (BSSE) effects, mostly between the C–H moieties constituting the arenes. We have carried out counterpoise-corrected optimizations and frequency calculations at the Hartree–Fock, B3LYP, MP2, and CISD levels of theory with several basis sets for a number of arenes. In all cases, correcting for intramolecular BSSE fixes the anomalous behavior of the correlated methods, whereas no significant differences are observed in the single-determinant case. Consequently, all systems studied are planar at all levels of theory. The effect of different intramolecular fragment definitions and the particular case of charged species, namely, cyclopentadienyl and indenyl anions, respectively, are also discussed

An assessment of gene prediction accuracy in large DNA sequences

One of the first useful products from the human genome will be a set of predicted genes. Besides its intrinsic scientific interest, the accuracy and completeness of this data set is of considerable importance for human health and medicine. Though progress has been made on computational gene identification in terms of both methods and accuracy evaluation measures, most of the sequence sets in which the programs are tested are short genomic sequences, and there is concern that these accuracy measures may not extrapolate well to larger, more challenging data sets. Given the absence of experimentally verified large genomic data sets, we constructed a semiartificial test set comprising a number of short single-gene genomic sequences with randomly generated intergenic regions. This test set, which should still present an easier problem than real human genomic sequence, mimics the approximately 200kb long BACs being sequenced. In our experiments with these longer genomic sequences, the accuracy of GENSCAN, one of the most accurate ab initio gene prediction programs, dropped significantly, although its sensitivity remained high. Conversely, the accuracy of similarity-based programs, such as GENEWISE, PROCRUSTES, and BLASTX was not affected significantly by the presence of random intergenic sequence, but depended on the strength of the similarity to the protein homolog. As expected, the accuracy dropped if the models were built using more distant homologs, and we were able to quantitatively estimate this decline. However, the specificities of these techniques are still rather good even when the similarity is weak, which is a desirable characteristic for driving expensive follow-up experiments. Our experiments suggest that though gene prediction will improve with every new protein that is discovered and through improvements in the current set of tools, we still have a long way to go before we can decipher the precise exonic structure of every gene in the human genome using purely computational methodology.

Comparative gene prediction in human and mouse

The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level with the mouse genome can help eliminate some of those false positives. Here we describe SGP2, a gene prediction program that combines ab initio gene prediction with TBLASTX searches between two genome sequences to provide both sensitive and specific gene predictions. The accuracy of SGP2 when used to predict genes by comparing the human and mouse genomes is assessed on a number of data sets, including single-gene data sets, the highly curated human chromosome 22 predictions, and entire genome predictions from ENSEMBL. Results indicate that SGP2 outperforms purely ab initio gene prediction methods. Results also indicate that SGP2 works about as well with 3x shotgun data as it does with fully assembled genomes. SGP2 provides a high enough specificity that its predictions can be experimentally verified at a reasonable cost. SGP2 was used to generate a complete set of gene predictions on both the human and mouse by comparing the genomes of these two species. Our results suggest that another few thousand human and mouse genes currently not in ENSEMBL are worth verifying experimentally.

Molecular modeling study of the binding and signaling properties of the TCRpMHC complex

The activation of the specific immune response against tumor cells is based on the recognition by the CD8+ Cytotoxic Τ Lymphocytes (CTL), of antigenic peptides (p) presented at the surface of the cell by the class I major histocompatibility complex (MHC). The ability of the so-called T-Cell Receptors (TCR) to discriminate between self and non-self peptides constitutes the most important specific control mechanism against infected cells. The TCR/pMHC interaction has been the subject of much attention in cancer therapy since the design of the adoptive transfer approach, in which Τ lymphocytes presenting an interesting response against tumor cells are extracted from the patient, expanded in vitro, and reinfused after immunodepletion, possibly leading to cancer regression. In the last decade, major progress has been achieved by the introduction of engineered lypmhocytes. In the meantime, the understanding of the molecular aspects of the TCRpMHC interaction has become essential to guide in vitro and in vivo studies. In 1996, the determination of the first structure of a TCRpMHC complex by X-ray crystallography revealed the molecular basis of the interaction. Since then, molecular modeling techniques have taken advantage of crystal structures to study the conformational space of the complex, and understand the specificity of the recognition of the pMHC by the TCR. In the meantime, experimental techniques used to determine the sequences of TCR that bind to a pMHC complex have been used intensively, leading to the collection of large repertoires of TCR sequences that are specific for a given pMHC. There is a growing need for computational approaches capable of predicting the molecular interactions that occur upon TCR/pMHC binding without relying on the time consuming resolution of a crystal structure. This work presents new approaches to analyze the molecular principles that govern the recognition of the pMHC by the TCR and the subsequent activation of the T-cell. We first introduce TCRep 3D, a new method to model and study the structural properties of TCR repertoires, based on homology and ab initio modeling. We discuss the methodology in details, and demonstrate that it outperforms state of the art modeling methods in predicting relevant TCR conformations. Two successful applications of TCRep 3D that supported experimental studies on TCR repertoires are presented. Second, we present a rigid body study of TCRpMHC complexes that gives a fair insight on the TCR approach towards pMHC. We show that the binding mode of the TCR is correctly described by long-distance interactions. Finally, the last section is dedicated to a detailed analysis of an experimental hydrogen exchange study, which suggests that some regions of the constant domain of the TCR are subject to conformational changes upon binding to the pMHC. We propose a hypothesis of the structural signaling of TCR molecules leading to the activation of the T-cell. It is based on the analysis of correlated motions in the TCRpMHC structure. - L'activation de la réponse immunitaire spécifique dirigée contre les cellules tumorales est basée sur la reconnaissance par les Lymphocytes Τ Cytotoxiques (CTL), d'un peptide antigénique (p) présenté à la suface de la cellule par le complexe majeur d'histocompatibilité de classe I (MHC). La capacité des récepteurs des lymphocytes (TCR) à distinguer les peptides endogènes des peptides étrangers constitue le mécanisme de contrôle le plus important dirigé contre les cellules infectées. L'interaction entre le TCR et le pMHC est le sujet de beaucoup d'attention dans la thérapie du cancer, depuis la conception de la méthode de transfer adoptif: les lymphocytes capables d'une réponse importante contre les cellules tumorales sont extraits du patient, amplifiés in vitro, et réintroduits après immunosuppression. Il peut en résulter une régression du cancer. Ces dix dernières années, d'importants progrès ont été réalisés grâce à l'introduction de lymphocytes modifiés par génie génétique. En parallèle, la compréhension du TCRpMHC au niveau moléculaire est donc devenue essentielle pour soutenir les études in vitro et in vivo. En 1996, l'obtention de la première structure du complexe TCRpMHC à l'aide de la cristallographie par rayons X a révélé les bases moléculaires de l'interaction. Depuis lors, les techniques de modélisation moléculaire ont exploité les structures expérimentales pour comprendre la spécificité de la reconnaissance du pMHC par le TCR. Dans le même temps, de nouvelles techniques expérimentales permettant de déterminer la séquence de TCR spécifiques envers un pMHC donné, ont été largement exploitées. Ainsi, d'importants répertoires de TCR sont devenus disponibles, et il est plus que jamais nécessaire de développer des approches informatiques capables de prédire les interactions moléculaires qui ont lieu lors de la liaison du TCR au pMHC, et ce sans dépendre systématiquement de la résolution d'une structure cristalline. Ce mémoire présente une nouvelle approche pour analyser les principes moléculaires régissant la reconnaissance du pMHC par le TCR, et l'activation du lymphocyte qui en résulte. Dans un premier temps, nous présentons TCRep 3D, une nouvelle méthode basée sur les modélisations par homologie et ab initio, pour l'étude de propriétés structurales des répertoires de TCR. Le procédé est discuté en détails et comparé à des approches standard. Nous démontrons ainsi que TCRep 3D est le plus performant pour prédire des conformations pertinentes du TCR. Deux applications à des études expérimentales des répertoires TCR sont ensuite présentées. Dans la seconde partie de ce travail nous présentons une étude de complexes TCRpMHC qui donne un aperçu intéressant du mécanisme d'approche du pMHC par le TCR. Finalement, la dernière section se concentre sur l'analyse détaillée d'une étude expérimentale basée sur les échanges deuterium/hydrogène, dont les résultats révèlent que certaines régions clés du domaine constant du TCR sont sujettes à un changement conformationnel lors de la liaison au pMHC. Nous proposons une hypothèse pour la signalisation structurelle des TCR, menant à l'activation du lymphocyte. Celle-ci est basée sur l'analyse des mouvements corrélés observés dans la structure du TCRpMHC.

Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling.

To investigate their role in receptor coupling to G(q), we mutated all basic amino acids and some conserved hydrophobic residues of the cytosolic surface of the alpha(1b)-adrenergic receptor (AR). The wild type and mutated receptors were expressed in COS-7 cells and characterized for their ligand binding properties and ability to increase inositol phosphate accumulation. The experimental results have been interpreted in the context of both an ab initio model of the alpha(1b)-AR and of a new homology model built on the recently solved crystal structure of rhodopsin. Among the twenty-three basic amino acids mutated only mutations of three, Arg(254) and Lys(258) in the third intracellular loop and Lys(291) at the cytosolic extension of helix 6, markedly impaired the receptor-mediated inositol phosphate production. Additionally, mutations of two conserved hydrophobic residues, Val(147) and Leu(151) in the second intracellular loop had significant effects on receptor function. The functional analysis of the receptor mutants in conjunction with the predictions of molecular modeling supports the hypothesis that Arg(254), Lys(258), as well as Leu(151) are directly involved in receptor-G protein interaction and/or receptor-mediated activation of the G protein. In contrast, the residues belonging to the cytosolic extensions of helices 3 and 6 play a predominant role in the activation process of the alpha(1b)-AR. These findings contribute to the delineation of the molecular determinants of the alpha(1b)-AR/G(q) interface.

Defect study of SnO2 nanostructures by cathodoluminescence analysis: Application to nanowires

Defects in SnO2 nanowires have been studied by cathodoluminescence, and the obtained spectra have been compared with those measured on SnO2 nanocrystals of different sizes in order to reveal information about point defects not determined by other characterization techniques. Dependence of the luminescence bands on the thermal treatment temperatures and pre-treatment conditions have been determined pointing out their possible relation, due to the used treatment conditions, with the oxygen vacancy concentration. To explain these cathodoluminescence spectra and their behavior, a model based on first-principles calculations of the surface oxygen vacancies in the different crystallographic directions is proposed for corroborating the existence of surface state bands localized at energy values compatible with the found cathodoluminescence bands and with the gas sensing mechanisms. CL bands centered at 1.90 and 2.20 eV are attributed to the surface oxygen vacancies 100° coordinated with tin atoms, whereas CL bands centered at 2.37 and 2.75 eV are related to the surface oxygen vacancies 130° coordinated. This combined process of cathodoluminescence and ab initio calculations is shown to be a powerful tool for nanowire defect analysis.

Vortices in atomic Bose-Einstein condensates in the large-gas-parameter region

In this work we compare the results of the Gross-Pitaevskii and modified Gross-Pitaevskii equations with ab initio variational Monte Carlo calculations for Bose-Einstein condensates of atoms in axially symmetric traps. We examine both the ground state and excited states having a vortex line along the z axis at high values of the gas parameter and demonstrate an excellent agreement between the modified Gross-Pitaevskii and ab initio Monte Carlo methods, both for the ground and vortex states.

Relativistic mean-field interaction with density-dependent meson-nucleon vertices based on microscopical calculations

Although ab initio calculations of relativistic Brueckner theory lead to large scalar isovector fields in nuclear matter, at present, successful versions of covariant density functional theory neglect the interactions in this channel. A new high-precision density functional DD-MEδ is presented which includes four mesons, σ, ω, δ, and ρ, with density-dependent meson-nucleon couplings. It is based to a large extent on microscopic ab initiocalculations in nuclear matter. Only four of its parameters are determined by adjusting to binding energies and charge radii of finite nuclei. The other parameters, in particular the density dependence of the meson-nucleon vertices, are adjusted to nonrelativistic and relativistic Brueckner calculations of symmetric and asymmetric nuclear matter. The isovector effective mass mp*−mn* derived from relativistic Brueckner theory is used to determine the coupling strength of the δ meson and its density dependence.

TCRep 3D: an automated in silico approach to study the structural properties of TCR repertoires.

TCRep 3D is an automated systematic approach for TCR-peptide-MHC class I structure prediction, based on homology and ab initio modeling. It has been considerably generalized from former studies to be applicable to large repertoires of TCR. First, the location of the complementary determining regions of the target sequences are automatically identified by a sequence alignment strategy against a database of TCR Vα and Vβ chains. A structure-based alignment ensures automated identification of CDR3 loops. The CDR are then modeled in the environment of the complex, in an ab initio approach based on a simulated annealing protocol. During this step, dihedral restraints are applied to drive the CDR1 and CDR2 loops towards their canonical conformations, described by Al-Lazikani et. al. We developed a new automated algorithm that determines additional restraints to iteratively converge towards TCR conformations making frequent hydrogen bonds with the pMHC. We demonstrated that our approach outperforms popular scoring methods (Anolea, Dope and Modeller) in predicting relevant CDR conformations. Finally, this modeling approach has been successfully applied to experimentally determined sequences of TCR that recognize the NY-ESO-1 cancer testis antigen. This analysis revealed a mechanism of selection of TCR through the presence of a single conserved amino acid in all CDR3β sequences. The important structural modifications predicted in silico and the associated dramatic loss of experimental binding affinity upon mutation of this amino acid show the good correspondence between the predicted structures and their biological activities. To our knowledge, this is the first systematic approach that was developed for large TCR repertoire structural modeling.

Nonempirical cluster-model study of the chemisorption of atomic hydrogen on the (111) surface of diamondlike crystals

The interaction of atomic hydrogen with C4H9, Si4H9, and Ge4H9 model clusters has been studied using all-electron and pseudopotential ab initio Hartree-Fock computations with basis sets of increasing flexibility. The results show that the effect of polarization functions is important in order to reproduce the experimental findings, but their inclusion only for the atoms directly involved in the chemisorption bond is usually sufficient. For the systems H-C4H9 and H-Si4H9 all-electron and pseudopotential results are in excellent agreement when basis sets of comparable quality are used. Besides, semiempirical modified-neglect-of-differential-overlap computations provide quite reliable results both for diamond and silicon and have been used to investigate larger model clusters. The results confirm the local nature of chemisorption and further justify the use of minimal X4H9 model clusters.

Evidence for oxygen-island formation on Al(111): Cluster-model theory and x-ray photoelectron spectroscopy

The O 1s x-ray photoelectron spectroscopy spectrum for Al(111)/O at 300 K shows two components whose behavior as a function of time and variation of detection angle are consistent with either (a) a surface species represented by the higher binding-energy (BE) component and a subsurface species represented by the lower BE component, or (b) small close-packed oxygen islands with the interior atoms represented by the lower BE component and the perimeter atoms by the higher BE component. We have modeled both situations using ab initio Hartree-Fock wave functions for clusters of Al and O atoms. For an O atom in a threefold site, it was found that a below-surface position gave a higher O 1s BE than an above-surface position, incompatible with interpretation (a). This change in the O 1s BE could arise because the bond for O to Al may have a more covalent character when the O is below the surface than when it is above the surface. We present evidence consistent with this view. An O adatom island with all the O atoms in threefold sites gives calculated O 1s BE's which are significantly higher for the perimeter O atoms. Further, the results for an isolated O island without the Al substrate present also give higher BE¿s for the perimeter atoms. Both these results are consistent with interpretation (b). Published scanning-tunneling-microscopy data supports the suggestion that the chemisorbed state consists of small, close-packed islands, whereas the presence of two vibrational modes in high-resolution electron-energy-loss spectroscopy data has been interpreted as representing surface and subsurface oxygen atoms. In light of the present results, we suggest that a vibrational interpretation in terms of interior and perimeter adatoms should be considered.

Evidence for two different bonding mechanisms of Al on Si(111)

By means of the ab initio cluster-model approach, we present theoretical evidence for two different mechanisms of bonding of atomic Al to Si(111). On the atop site (T1) the interaction of atomic Al to Si(111) is characteristic of an ionic bond whereas interaction above the threefold eclipsed site (T4) leads to the formation of a typical covalent bond. Moreover, both sites have a similar interaction energy if electronic correlation effects are included. While the conclusions regarding the nature of the chemisorption bond in the two sites do not depend either on the cluster-model size, the kind of embedding hydrogen atoms used, or the quality of the wave function (Hartree-Fock or configuration interaction), the chemisorption energy depends strongly on the wave function used. In fact, inclusion of correlation energy is necessary to properly describe the interaction energies.

Electronic structure and properties of AlN

The electronic structure of the wurtzite-type phase of aluminum nitride has been investigated by means of periodic ab initio Hartree-Fock calculations. The binding energy, lattice parameters (a,c), and the internal coordinate (u) have been calculated. All structural parameters are in excellent agreement with the experimental data. The electronic structure and bonding in AlN are analyzed by means of density-of-states projections and electron-density maps. The calculated values of the bulk modulus, its pressure derivative, the optical-phonon frequencies at the center of the Brillouin zone, and the full set of elastic constants are in good agreement with the experimental data.

Extent and limitations of density functional theory in describing magnetic systems

The performance of density-functional theory to solve the exact, nonrelativistic, many-electron problem for magnetic systems has been explored in a new implementation imposing space and spin symmetry constraints, as in ab initio wave function theory. Calculations on selected systems representative of organic diradicals, molecular magnets and antiferromagnetic solids carried out with and without these constraints lead to contradictory results, which provide numerical illustration on this usually obviated problem. It is concluded that the present exchange-correlation functionals provide reasonable numerical results although for the wrong physical reasons, thus evidencing the need for continued search for more accurate expressions.