Algorithm engineering for optimal alignment of protein structure distance matrices

Protein structural alignment is an important problem in computational biology. In this paper, we present first successes on provably optimal pairwise alignment of protein inter-residue distance matrices, using the popular Dali scoring function. We introduce the structural alignment problem formally, which enables us to express a variety of scoring functions used in previous work as special cases in a unified framework. Further, we propose the first mathematical model for computing optimal structural alignments based on dense inter-residue distance matrices. We therefore reformulate the problem as a special graph problem and give a tight integer linear programming model. We then present algorithm engineering techniques to handle the huge integer linear programs of real-life distance matrix alignment problems. Applying these techniques, we can compute provably optimal Dali alignments for the very first time

Synthetic metallomolecules as agents for the control of DNA structure

This tutorial review summarises B-DNA structure and metallomolecule binding modes and illustrates some DNA structures induced by molecules containing metallic cations. The effects of aquated metal ions, cobalt amines, ruthenium octahedral metal complexes, metallohelicates and platinum complexes such as cis-platin are discussed alongside the techniques of NMR, X-ray crystallography, gel electrophoresis, circular dichroism, linear dichroism and molecular dynamics. The review will be of interest to people interested in both DNA structure and roles of metallomolecules in biological systems

NMR investigations of the interaction between the azo-dye sunset yellow and Fluorophenol

The interaction of small molecules with larger noncovalent assemblies is important across a wide range of disciplines. Here, we apply two complementary NMR spectroscopic methods to investigate the interaction of various fluorophenol isomers with sunset yellow. This latter molecule is known to form noncovalent aggregates in isotropic solution, and form liquid crystals at high concentrations. We utilize the unique fluorine-19 nucleus of the fluorophenol as a reporter of the interactions via changes in both the observed chemical shift and diffusion coefficients. The data are interpreted in terms of the indefinite self-association model and simple modifications for the incorporation of a second species into an assembly. A change in association mode is tentatively assigned whereby the fluorophenol binds end-on with the sunset yellow aggregates at low concentration and inserts into the stacks at higher concentrations

Phase Behavior of Columnar DNA Assemblies

The pair interaction between two stiff parallel linear DNA molecules depends not only on the distance between their axes but on their azimuthal orientation. The positional and orientational order in columnar B-DNA assemblies in solution is investigated, based on the DNA-DNA electrostatic pair potential that takes into account DNA helical symmetry and the amount and distribution of adsorbed counterions. A phase diagram obtained by lattice sum calculations predicts a variety of positionally and azimuthally ordered phases and bundling transitions strongly depending on the counterion adsorption patterns.Comment: 4 pages, 3 figures, submitted to PR

Influence of structural isomerism and fluorine atom substitution on the self-association of naphthoic acid

The self-association of small aromatic systems driven by π-π stacking and hydrophobic interactions is well known. Understanding the nature of these interactions is important if they are to be used to control association. Here, we present results of an NMR study into the self-association of two isomers of naphthoic acid along with an investigation into the role of a fluorine substituent on that self- association. We interpret the results in terms of a simple isodesmic model of self- association and show that the addition of the fluorine atom appears to increase the stability of the aggregates by an order of magnitude (e.g. 1-naphothic acid vs 4- fluoro-1-naphthoic acid Keq = 0.05 increases to 0.35 M-1), a result which is supported by computational studies in the literature on the role of substituent effects on interaction energy. The use of fluorinated isomers to probe the assembly is also presented, with differing trends in fluorine-19 chemical shifts observed depending on the isomer substitution pattern

Allosteric Regulation of Fibronectin/α5β1 Interaction by Fibronectin-Binding MSCRAMMs

Citation: Liang, X. W., Garcia, B. L., Visai, L., Prabhakaran, S., Meenan, N. A. G., Potts, J. R., . . . Hook, M. (2016). Allosteric Regulation of Fibronectin/alpha(5)beta(1) Interaction by Fibronectin-Binding MSCRAMMs. Plos One, 11(7), 17. doi:10.1371/journal.pone.0159118Adherence ofmicrobes to host tissues is a hallmark of infectious disease and is often mediated by a class of adhesins termed MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules). Numerous pathogens express MSCRAMMs that specifically bind the heterodimeric human glycoprotein fibronectin (Fn). In addition to roles in adhesion, Fn-binding MSCRAMMs exploit physiological Fn functions. For example, several pathogens can invade host cells by a mechanism whereby MSCRAMM-bound Fn bridges interaction with alpha(5)beta(1) integrin. Here, we investigate two Fn-binding MSCRAMMs, FnBPA (Staphylococcus aureus) and BBK32 (Borrelia burgdorferi) to probe structure-activity relationships of MSCRAMM-induced Fn/alpha(5)beta(1) integrin activation. Circular dichroism, fluorescence resonance energy transfer, and dynamic light scattering techniques uncover a conformational rearrangement of Fn involving domains distant from the MSCRAMM binding site. Surface plasmon resonance experiments demonstrate a significant enhancement of Fn/alpha(5)beta(1) integrin affinity in the presence of FnBPA or BBK32. Detailed kinetic analysis of these interactions reveal that this change in affinity can be attributed solely to an increase in the initial Fn/alpha(5)beta(1) on-rate and that this rate-enhancement is dependent on high-affinity Fn-binding by MSCRAMMs. These data implicate MSCRAMM-induced perturbation of specific intramolecular contacts within the Fn heterodimer resulting in activation by exposing previously cryptic alpha(5)beta(1) interaction motifs. By correlating structural changes in Fn to a direct measurement of increased Fn/alpha(5)beta(1) affinity, this work significantly advances our understanding of the structural basis for the modulation of integrin function by Fn-binding MSCRAMMs

A simple and fast heuristic for protein structure comparison

Background Protein structure comparison is a key problem in bioinformatics. There exist several methods for doing protein comparison, being the solution of the Maximum Contact Map Overlap problem (MAX-CMO) one of the alternatives available. Although this problem may be solved using exact algorithms, researchers require approximate algorithms that obtain good quality solutions using less computational resources than the formers. Results We propose a variable neighborhood search metaheuristic for solving MAX-CMO. We analyze this strategy in two aspects: 1) from an optimization point of view the strategy is tested on two different datasets, obtaining an error of 3.5%(over 2702 pairs) and 1.7% (over 161 pairs) with respect to optimal values; thus leading to high accurate solutions in a simpler and less expensive way than exact algorithms; 2) in terms of protein structure classification, we conduct experiments on three datasets and show that is feasible to detect structural similarities at SCOP's family and CATH's architecture levels using normalized overlap values. Some limitations and the role of normalization are outlined for doing classification at SCOP's fold level. Conclusion We designed, implemented and tested.a new tool for solving MAX-CMO, based on a well-known metaheuristic technique. The good balance between solution's quality and computational effort makes it a valuable tool. Moreover, to the best of our knowledge, this is the first time the MAX-CMO measure is tested at SCOP's fold and CATH's architecture levels with encouraging results. Software is available for download at http://modo.ugr.es/jrgonzalez/msvns4maxcmo webcite.This work is supported by Projects HeuriCosc TIN2005-08404-C04-01, HeuriCode TIN2005-08404-C04-03, both from the Spanish Ministry of Education and Science. JRG acknowledges financial support from Project TIC2002-04242-C03-02. Authors thank N. Krasnogor and ProCKSi project (BB/C511764/1) for their support

Time-Driven Activity-Based Costing for Cervical Myelopathy Surgery: A Step Towards Total Episode Costs

INTRODUCTION: Time-driven activity-based costing (TDABC) is a highly accurate method for determining the true cost of delivering a healthcare service. However, TDABC is most often applied to a singular phase of care such as an outpatient visit or a surgical event. Here we broaden the scope by using TDABC to estimate the costs of surgically treating cervical myelopathy - from the moment of surgical scheduling until post-operative hospital discharge. METHODS: In a single-center retrospective study at a large tertiary academic institution, TDABC was employed to measure pre-operative, intra-operative, and post-operative (inpatient) costs for 63 patients undergoing elective surgery for cervical myelopathy. Cost patterns among different surgical approaches (anterior, posterior, anterior/posterior) were analyzed using generalized linear models and the Kruskal-Wallis test. RESULTS: 63 consecutive patients who underwent elective surgery for cervical myelopathy were examined (anterior approach: 36.5%, n=23; posterior approach: 54.0%, n=34; anterior/posterior approach: 9.5%, n=6). The average pre-operative, intraoperative, and postoperative costs were $352.83 ±$205, $10,809.09 ±$6052.69, and $5327.07 ±$5114.78, respectively. The average total episode cost for all cases was $16,488.99 ±$8,181,777. Kruskal-Wallis analysis revealed that total episode cost for the anterior-posterior approach was significantly higher than for both the anterior (p\u3c 0.001) and posterior approaches (p\u3c 0.05), while the total episode cost for the anterior approach was significantly less than that of the posterior (p\u3c 0.001). CONCLUSION: We have demonstrated the feasibility of TDABC for estimating a large fraction of total episode costs for the surgical treatment of cervical myelopathy. This may also be the first attempt at understanding episode costs across multiple surgical options for a given spinal diagnosis, which will be relevant as condition-based bundled payments emerge. As expected, anterior cervical surgeries incurred lower costs than posterior surgeries, which incurred lower costs than anterior-posterior surgeries

Tableau-based protein substructure search using quadratic programming

<p>Abstract</p> <p>Background</p> <p>Searching for proteins that contain similar substructures is an important task in structural biology. The exact solution of most formulations of this problem, including a recently published method based on tableaux, is too slow for practical use in scanning a large database.</p> <p>Results</p> <p>We developed an improved method for detecting substructural similarities in proteins using tableaux. Tableaux are compared efficiently by solving the quadratic program (QP) corresponding to the quadratic integer program (QIP) formulation of the extraction of maximally-similar tableaux. We compare the accuracy of the method in classifying protein folds with some existing techniques.</p> <p>Conclusion</p> <p>We find that including constraints based on the separation of secondary structure elements increases the accuracy of protein structure search using maximally-similar subtableau extraction, to a level where it has comparable or superior accuracy to existing techniques. We demonstrate that our implementation is able to search a structural database in a matter of hours on a standard PC.</p

Is Anterior Cervical Discectomy and Fusion More Expensive at Quaternary Care Centers? An Application of Time-Driven Activity-Based Costing

OBJECTIVE: Hospital setting is postulated to be a key driver of cost variation for neurosurgical procedures. Limitations in contemporary costing methodologies have led to the development of time-driven activity-based costing (TDABC). This study applies TDABC to anterior cervical discectomy and fusion (ACDF) to compare intraoperative costs at quaternary care centers versus satellite hospitals affiliated with the same health network. METHODS: Nine hundred and fifty-eight ACDF cases performed at two quaternary care hospitals (n = 806) and six satellite hospitals (n = 152) were reviewed. Process maps were created to map the intraoperative episode, and TDABC methodology was used to calculate true surgical costs, including supply (e.g., implants, consumables) and personnel costs (e.g., per minute wages of all personnel types involved in care delivery). Software was developed to automate the extraction of this information from the electronic medical record. Multivariable logistic and linear regression models assessed predictors of high cost surgeries and the influence of hospital setting on total costs, adjusting for confounders. RESULTS: Quaternary hospitals had significantly lower total intraoperative costs compared to satellite hospitals ($6,773 ±$2,664 vs. $8,862 ±$3,690, P \u3c 0.001), with supply costs driving the difference. Among all hospital sites, supply cost, and personnel cost comprised most of the total cost. Satellite hospitals also had a 6.55-fold higher likelihood of performing high-cost surgeries (P \u3c 0.001). CONCLUSIONS: ACDFs were less expensive at quaternary care centers than at satellite hospitals, challenging assumptions about lower costs in satellite or community settings. Methodologies such as ours may establish a foundation for identifying which surgeries are most amenable to community-based care