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41.
Protein co-evolution under structural and functional constraints necessitates the preservation of important interactions. Identifying functionally important regions poses many obstacles in protein engineering efforts. In this paper, we present a bioinformatics-inspired approach (residue correlation analysis, RCA) for predicting functionally important domains from protein family sequence data. RCA is comprised of two major steps: (i) identifying pairs of residue positions that mutate in a coordinated manner, and (ii) using these results to identify protein regions that interact with an uncommonly high number of other residues. We hypothesize that strongly correlated pairs result not only from contacting pairs, but also from residues that participate in conformational changes involved during catalysis or important interactions necessary for retaining functionality. The results show that highly mobile loops that assist in ligand association/dissociation tend to exhibit high correlation. RCA results exhibit good agreement with the findings of experimental and molecular dynamics studies for the three protein families that are analyzed: (i) DHFR (dihydrofolate reductase), (ii) cyclophilin, and (iii) formyl-transferase. Specifically, the specificity (percentage of correct predictions) in all three cases is substantially higher than those obtained by entropic measures or contacting residue pairs. In addition, we use our approach in a predictive fashion to identify important regions of a transmembrane amino acid transporter protein for which there is limited structural and functional information available. 相似文献
42.
A simple molecular model for the thermodynamic behavior of non-polar solutes in water and in aqueous solutions of protein denaturants is presented. Three contributions are considered: (i) combinatorial arising from the mixing process, (ii) interactional characterizing the molecular interactions occurring in the mixture and (iii) a contribution originating from the structural changes occurring in the first shell of water molecules around the solute. The latter is modeled assuming that water molecules in contact with the solute are involved in a chemical equilibrium between two states. The model describes well the temperature and denaturant concentration dependences of the Gibbs energies of solution and transfer for benzene, toluene and alkanes in water and aqueous solutions of urea and guanidine hydrochloride. Model parameters are physically meaningful, allowing a discussion of the molecular interactions involved. A preferential solvation of the solute by the denaturant is found. However, the non-polar solute-denaturant interaction is not specific, i.e. leading to a distinct chemical entity. Urea and guanidine hydrochloride are non-polar solubilizing agents because their interactions with the solute are less unfavorable than those between water and the solute. 相似文献
43.
Costas Demetzos 《AAPS PharmSciTech》2015,16(3):491-495
Biophysics and thermodynamics are considered as the scientific milestones for investigating the properties of materials. The relationship between the changes of temperature with the biophysical variables of biomaterials is important in the process of the development of drug delivery systems. Biophysics is a challenge sector of physics and should be used complementary with the biochemistry in order to discover new and promising technological platforms (i.e., drug delivery systems) and to disclose the ‘silence functionality’ of bio-inspired biological and artificial membranes. Thermal analysis and biophysical approaches in pharmaceuticals present reliable and versatile tools for their characterization and for the successful development of pharmaceutical products. The metastable phases of self-assembled nanostructures such as liposomes should be taken into consideration because they represent the thermal events can affect the functionality of advanced drug delivery nano systems. In conclusion, biophysics and thermodynamics are characterized as the building blocks for design and development of bio-inspired drug delivery systems.KEY WORDS: biophysics, drug delivery nano systems, pharmaceutics, thermal analysis, thermodynamics 相似文献
44.
Costas Mitsopoulos Amanda C. Schierz Paul Workman Bissan Al-Lazikani 《PLoS computational biology》2015,11(12)
The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance of the network environment, it is neglected during target selection for drug discovery. Here, we present the first systematic, comprehensive computational analysis of topological, community and graphical network parameters of the human interactome and identify discriminatory network patterns that strongly distinguish drug targets from the interactome as a whole. Importantly, we identify striking differences in the network behavior of targets of cancer drugs versus targets from other therapeutic areas and explore how they may relate to successful drug combinations to overcome acquired resistance to cancer drugs. We develop, computationally validate and provide the first public domain predictive algorithm for identifying druggable neighborhoods based on network parameters. We also make available full predictions for 13,345 proteins to aid target selection for drug discovery. All target predictions are available through canSAR.icr.ac.uk. Underlying data and tools are available at https://cansar.icr.ac.uk/cansar/publications/druggable_network_neighbourhoods/. 相似文献
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Changes in plasma amino acid levels in a euryhaline fish exposed to different environmental salinities 总被引:1,自引:0,他引:1
Cláudia Aragão Benjamín Costas Luis Vargas-Chacoff Ignacio Ruiz-Jarabo Maria Teresa Dinis Juan Miguel Mancera Luís E. C. Conceição 《Amino acids》2010,38(1):311-317
Previous studies have shown that Senegalese sole is partially euryhaline in the juvenile phase, being able to adapt to a wide
range of salinities in a short-time period, due to changes at the osmoregulatory and metabolic level. This study aimed to
assess the effects of acclimation of sole to a wide range of salinities, with a special emphasis on the role of plasma amino
acids during this process. Sole juveniles were acclimated for 2 weeks to different salinities: 5, 15, 25, 38, and 55 g L−1. Plasma levels of cortisol, glucose, osmolality, and free amino acids were assessed at the end. Changes in plasma levels
of cortisol, glucose, and amino acids indicate that fish reared at 5 and 55 g L−1 were facing extra energy costs. Amino acids seem to play an important role during salinity acclimation, either as energy
sources or as important osmolytes for cell volume regulation. 相似文献
48.
Background
Saccharomyces cerevisiae is the first eukaryotic organism for which a multi-compartment genome-scale metabolic model was constructed. Since then a sequence of improved metabolic reconstructions for yeast has been introduced. These metabolic models have been extensively used to elucidate the organizational principles of yeast metabolism and drive yeast strain engineering strategies for targeted overproductions. They have also served as a starting point and a benchmark for the reconstruction of genome-scale metabolic models for other eukaryotic organisms. In spite of the successive improvements in the details of the described metabolic processes, even the recent yeast model (i.e., i MM904) remains significantly less predictive than the latest E. coli model (i.e., i AF1260). This is manifested by its significantly lower specificity in predicting the outcome of grow/no grow experiments in comparison to the E. coli model. 相似文献49.
Tim J Dexter David Sims Costas Mitsopoulos Alan Mackay Anita Grigoriadis Amar S Ahmad Marketa Zvelebil 《BMC systems biology》2010,4(1):127
Background
Genomic copy number changes and regional alterations in epigenetic states have been linked to grade in breast cancer. However, the relative contribution of specific alterations to the pathology of different breast cancer subtypes remains unclear. The heterogeneity and interplay of genomic and epigenetic variations means that large datasets and statistical data mining methods are required to uncover recurrent patterns that are likely to be important in cancer progression. 相似文献50.
Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbial strains are widely in use. However, these methods rely on surrogate biological objectives (e.g., maximize growth rate or minimize metabolic adjustments) and do not make use of flux measurements often available for the wild-type strain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactions in the metabolic model depending upon whether their flux values must increase, decrease or become equal to zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples, etc. of reactions. This leads to the identification of a sufficient and non-redundant set of fluxes that must change (i.e., MUST set) to meet a pre-specified overproduction target. Starting with this set we subsequently extract a minimal set of fluxes that must actively be forced through genetic manipulations (i.e., FORCE set) to ensure that all fluxes in the network are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in Escherichia coli using the most recent in silico E. coli model, iAF1260. The method not only recapitulates existing engineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathways distant from the last steps of succinate synthesis. 相似文献