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Site-specific DNA-protein interactions can be studied using experimental and computational methods. Experimental approaches typically analyze a protein-DNA interaction by measuring the free energy of binding under a variety of conditions. Computational methods focus on alignments of known binding sites for a protein, and, from these alignments, make estimates of the binding energy. Understanding the relationship between these two perspectives, and finding ways to improve both, is a major challenge of modern molecular biology.
BACKGROUND: An important challenge in eukaryotic gene prediction is accurate identification of alternatively spliced exons. Functional transcripts can go undetected in gene expression studies when alternative splicing only occurs under specific biological conditions. Non-expression based computational methods support identification of rarely expressed transcripts. RESULTS: A non-expression based statistical method is presented to annotate alternatively spliced exons using a single genome sequence and evidence from cross-species sequence conservation. The computational method is implemented in the program ExAlt and an analysis of prediction accuracy is given for Drosophila melanogaster. CONCLUSION: ExAlt identifies the structure of most alternatively spliced exons in the test set and cross-species sequence conservation is shown to improve the precision of predictions. The software package is available to run on Drosophila genomes to search for new cases of alternative splicing.
A computational method of predicting all the polymorphs of an organic molecule would be a valuable complement to polymorph screening in the developmental phase. Such a computational method is in its early stages of development, and the current methodologies, which are based on searches for the most stable lattice structure, are critically reviewed. This crude thermodynamic approach generally overestimates the propensity for polymorphism, at least for most of the molecules studied so far, showing the need to model kinetic effects as well as to refine the thermodynamic models. Although the ultimate goal of these studies is still far off, computational predictions of crystal structures have proved useful in aiding the characterisation of polymorphs from powder X-ray data, and in providing insights into the range of types of packing that may be adopted by a given molecule. Thus, computational studies already have the potential to be a valuable tool in pharmaceutical solid state science.
RATIONALE AND OBJECTIVES: The authors developed and subjectively evaluated an interslice compression algorithm that explores the redundancy among adjacent slices of an x-ray computed tomography (CT) scan. This algorithm has been compared to an intraslice compression algorithm based on the two-dimensional discrete cosine transform. METHODS: Nine x-ray CT head images from three patients were compressed with this interslice method at compression ratios of 5:1, 10:1, and 15:1. The same images were also compressed with the intraslice method at the same ratios. Six radiologists judged quality of randomly selected compressed and decompressed images compared to that of the originals. The evaluation data were analyzed statistically with the analysis of variance and Tukey's multiple comparison. Kappa-like statistics (Williams index and O'Connell and Dobson indexes) were also calculated to measure the agreement among readers beyond the amount expected by chance. RESULTS: The interslice coding algorithm showed significantly better quality than the intraslice method at significance level 0.05, even though there was no difference in the objective distortion measure (signal-to-noise ratio). Also, the quality of 10:1 compressed images with the interslice coding algorithm was not significantly different from that of the originals at level 0.05. While large variations in agreement occurred among readers, the overall agreement was statistically significant. CONCLUSIONS: By using adjacent slice information in compressing x-ray CT images, significantly better quality in compressed and decompressed images was achieved. While 10:1 compressed images with the interslice algorithm were not significantly different from the originals in quality at level 0.05, effect on diagnostic accuracy remains to be investigated.
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We describe the development and application of a computational method for the prediction and rationalization of pKa values of ionizable residues in proteins, based on ab initio quantum mechanics (QM) and the effective fragment potential (EFPs) method (a hybrid QM/MM method). The theoretical developments include (1) a covalent boundary method based on frozen localized orbitals, (2) divide-and-conquer methods for the ab initio computation of protein EFPs consisting of multipoles up to octupoles and dipole polarizability tensors, (3) a method for computing vibrational free energies for a localized molecular region, and (4) solutions of the polarized continuum model of bulk solvation equations for protein-sized systems. The QM-based pKa prediction method is one of the most accurate methods currently available and can be used in cases where other pKa prediction methods fail. Preliminary analysis of the computed results indicate that many pKa values (1) are primarily determined by hydrogen bonds rather than long-range charge-charge interactions and (2) are relatively insensitive to large-scale dynamical fluctuations of the protein structure.
A new method to aid the determination of structures of sterically crowded molecules in the gas phase by dynamically linking the gas-phase electron diffraction (GED) refinement process with computational methods has been developed. The procedure involves refining the heavy-atom skeleton of the molecule using the GED data while continually updating the light-atom positions during the refinement using computational methods, in this case molecular mechanics. This removes errors associated with the assumption of local symmetry for the light-atom groups, which can affect the final values of the heavy-atom parameters. The refinement of the molecular structure of tri-tert-butyl phosphine oxide has been used to illustrate this new technique, which we call the DYNAMITE (DYNAMic Interaction of Theory and Experiment) method. Re-examination of the structure using this method has resulted in a shorter P-O distance than was found in a less sophisticated anaylsis, and is consistent with the molecule being regarded as O=PBut3, rather than O(-)-P+But3.
A computational approach to determine electrostatic interaction and gravitational potentials by performing direct numerical integration is presented. The potential is expanded using finite-element functions of arbitrary order. The method does not involve any solutions of systems of linear equations. The potential is instead obtained as a sum of differential contributions. Thus, no boundary conditions for the potential are needed. It is computationally efficient and well suited for parallel computers, since the innermost loops constitute matrix multiplications and the outer ones can be used as parallel indices. Without using prescreening or other computational tricks to speed up the calculation, the algorithm scales as N4/3 where N denotes the grid size.
UNLABELLED: This paper evaluates the communication of information to physicians who provide off-hours coverage to inpatients in two Family Practice residency programs. METHOD: To describe the importance and accessibility of clinical information used by on-call residents in covering hospital patients, we administered a questionnaire. Then following the use of a new computerized sign-out system in one of the programs, residents filled out the same questionnaire again. RESULTS: Residents felt that a "to do" list and information about the patient's "code status" were the most important data desired from sign-out sheets. However, 69% of residents in both programs felt that provision of this information was normally poor. Nearly all of the residents in Buffalo, using an entirely handwritten sign-out sheet, felt it was in need of improvement. Residents in Pittsburgh, using a summary aided by the hospital's computer print-out, felt this need much less acutely. After implementation of a new computerized sign-out sheet in Buffalo, residents indicated a slightly higher level of satisfaction. The work of data entry and re-entry into the computer was unpopular and inefficient. CONCLUSION: The present method of transferring information at the end of a work day is not satisfactory for residents. Provision of data summaries from existing hospital information systems is a good first step in improving data transfer. A further study of more comprehensive automated sign-out systems is important, because of the increasing discontinuity of house officer care.
Microwave tumor ablation (MTA) offers a new approach for the treatment of hepatic neoplastic disease. Reliable and accurate information regarding the heat distribution inside biological tissue subjected to microwave thermal ablation is important for the efficient design of microwave applicators and for optimizing experiments, which aim to assess the effects of therapeutic treatments. Currently there are a variety of computational methods based on different vascular structures in tissue, which aim to model heat distribution during ablation. This paper presents results obtained from two such computational models for temperature distributions produced by a clinical 2.45 GHz MTA applicator immersed in unperfused ex vivo bovine liver, and compares them with measured results from a corresponding ex vivo experiment. The computational methods used to model the temperature distribution in tissue caused by the insertion of a 5.6 mm diameter "wandlike" microwave applicator are the Green's function method and the finite element method (FEM), both of which provide solutions of the heat diffusion partial differential equation. The results obtained from the coupled field simulations are shown to be in good agreement with a simplified analysis based on the bio-heat equation and with ex vivo measurements of the heat distribution produced by the clinical MTA applicator.
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