Cuesta J.A.,Grupo Interdisciplinar de Sistemas Complejos GISC |
Cuesta J.A.,Charles III University of Madrid |
Cuesta J.A.,Institute for Biocomputation and Physics of Complex Systems |
Manrubia S.,Grupo Interdisciplinar de Sistemas Complejos GISC |
Manrubia S.,CSIC - National Center for Biotechnology
Journal of Theoretical Biology | Year: 2017
A quantitative characterization of the relationship between molecular sequence and structure is essential to improve our understanding of how function emerges. This particular genotype-phenotype map has been often studied in the context of RNA sequences, with the folded configurations standing as a proxy for the phenotype. Here, we count the secondary structures of circular RNAs of length n and calculate the asymptotic distributions of different structural moieties, such as stems or hairpin loops, by means of symbolic combinatorics. Circular RNAs differ in essential ways from their linear counterparts. From the mathematical viewpoint, the enumeration of the corresponding secondary structures demands the use of combinatorial techniques additional to those used for linear RNAs. The asymptotic number of secondary structures for circular RNAs grows as ann−5/2, with a depending on particular constraints applied to the secondary structure. As it occurs with linear RNA, the abundance of any structural moiety is normally distributed in the limit n→∞, with a mean and a variance that increase linearly with n. © 2017 Elsevier Ltd
Catalan P.,Grupo Interdisciplinar de Sistemas Complejos GISC |
Catalan P.,Charles III University of Madrid |
Arias C.F.,Grupo Interdisciplinar de Sistemas Complejos GISC |
Cuesta J.A.,Grupo Interdisciplinar de Sistemas Complejos GISC |
And 5 more authors.
Biology Direct | Year: 2017
Background: Wright's metaphor of the fitness landscape has shaped and conditioned our view of the adaptation of populations for almost a century. Since its inception, and including criticism raised by Wright himself, the concept has been surrounded by controversy. Among others, the debate stems from the intrinsic difficulty to capture important features of the space of genotypes, such as its high dimensionality or the existence of abundant ridges, in a visually appealing two-dimensional picture. Two additional currently widespread observations come to further constrain the applicability of the original metaphor: the very skewed distribution of phenotype sizes (which may actively prevent, due to entropic effects, the achievement of fitness maxima), and functional promiscuity (i.e. the existence of secondary functions which entail partial adaptation to environments never encountered before by the population). Results: Here we revise some of the shortcomings of the fitness landscape metaphor and propose a new "scape" formed by interconnected layers, each layer containing the phenotypes viable in a given environment. Different phenotypes within a layer are accessible through mutations with selective value, while neutral mutations cause displacements of populations within a phenotype. A different environment is represented as a separated layer, where phenotypes may have new fitness values, other phenotypes may be viable, and the same genotype may yield a different phenotype, representing genotypic promiscuity. This scenario explicitly includes the many-to-many structure of the genotype-to-phenotype map. A number of empirical observations regarding the adaptation of populations in the light of adaptive multiscapes are reviewed. Conclusions: Several shortcomings of Wright's visualization of fitness landscapes can be overcome through adaptive multiscapes. Relevant aspects of population adaptation, such as neutral drift, functional promiscuity or environment-dependent fitness, as well as entropic trapping and the concomitant impossibility to reach fitness peaks are visualized at once. Adaptive multiscapes should aid in the qualitative understanding of the multiple pathways involved in evolutionary dynamics. Reviewers: This article was reviewed by Eugene Koonin and Ricard Solé. © 2017 The Author(s).
Bocanegra R.,Autonomous University of Madrid |
Nevot M.,Hospital Germans Trias i Pujol |
Domenech R.,University Miguel Hernández |
Lopez I.,Autonomous University of Madrid |
And 10 more authors.
PLoS ONE | Year: 2011
Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity. © 2011 Bocanegra et al.
Rosa A.,Institute for Biocomputation and Physics of Complex Systems |
Becker N.B.,CNRS Physics Laboratory |
Everaers R.,CNRS Physics Laboratory
Biophysical Journal | Year: 2010
Fluorescence in-situ hybridization (FISH) and chromosome conformation capture (3C) are two powerful techniques for investigating the three-dimensional organization of the genome in interphase nuclei. The use of these techniques provides complementary information on average spatial distances (FISH) and contact probabilities (3C) for specific genomic sites. To infer the structure of the chromatin fiber or to distinguish functional interactions from random colocalization, it Is useful to compare experimental data to predictions from statistical fiber models. The current estimates of the fiber stiffness derived from FISH and 3C differ by a factor of 5. They are based on the wormlike chain model and a heuristic modification of the ShimadaYamakawa theory of looping for unkinkable, unconstrained, zero-diameter filaments. Here, we provide an extended theoretical and computational framework to explain the currently available experimental data for various species on the basis of a unique, minimal model of decondensing chromosomes: a kinkable, topologically constraint, semiflexible polymer with the (FISH) Kuhn length of /K = 300 nm, 10 kinks per Mbp, and a contact distance of 45 nm. In particular: 1), we reconsider looping of finite-diameter filaments on the basis of an analytical approximation (novel, to our knowledge) of the wormlike chain radial density and show that unphysically large contact radii would be required to explain the 3C data based on the FISH estimate of the fiber stiffness; 2), we demonstrate that the observed interaction frequencies at short genomic lengths can be explained by the presence of a low concentration of curvature defects (kinks); and 3), we show that the most recent experimental 3C data for human chromosomes are in quantitative agreement with interaction frequencies extracted from our simulations of topologically confined model chromosomes. © 2010 by the Biophysical Society.
Guerrero G.D.,University of Chile |
Imbernon B.,San Antonio de Murcia Catholic University |
Perez-Sanchez H.,San Antonio de Murcia Catholic University |
Sanz F.,Institute for Biocomputation and Physics of Complex Systems |
And 2 more authors.
BioMed Research International | Year: 2014
Bioinformatics is an interdisciplinary research field that develops tools for the analysis of large biological databases, and, thus, the use of high performance computing (HPC) platforms is mandatory for the generation of useful biological knowledge. The latest generation of graphics processing units (GPUs) has democratized the use of HPC as they push desktop computers to cluster-level performance. Many applications within this field have been developed to leverage these powerful and low-cost architectures. However, these applications still need to scale to larger GPU-based systems to enable remarkable advances in the fields of healthcare, drug discovery, genome research, etc. The inclusion of GPUs in HPC systems exacerbates power and temperature issues, increasing the total cost of ownership (TCO). This paper explores the benefits of volunteer computing to scale bioinformatics applications as an alternative to own large GPU-based local infrastructures. We use as a benchmark a GPU-based drug discovery application called BINDSURF that their computational requirements go beyond a single desktop machine. Volunteer computing is presented as a cheap and valid HPC system for those bioinformatics applications that need to process huge amounts of data and where the response time is not a critical factor. © 2014 Ginés D. Guerrero et al.
Tapia-Rojo R.,University of Zaragoza |
Tapia-Rojo R.,Institute for Biocomputation and Physics of Complex Systems |
Mazo J.J.,University of Zaragoza |
Hernandez J.A.,Midwestern University |
And 6 more authors.
PLoS Computational Biology | Year: 2014
The identification of protein binding sites in promoter sequences is a key problem to understand and control regulation in biochemistry and biotechnological processes. We use a computational method to analyze promoters from a given genome. Our approach is based on a physical model at the mesoscopic level of protein-DNA interaction based on the influence of DNA local conformation on the dynamics of a general particle along the chain. Following the proposed model, the joined dynamics of the protein particle and the DNA portion of interest, only characterized by its base pair sequence, is simulated. The simulation output is analyzed by generating and analyzing the Free Energy Landscape of the system. In order to prove the capacity of prediction of our computational method we have analyzed nine promoters of Anabaena PCC 7120. We are able to identify the transcription starting site of each of the promoters as the most populated macrostate in the dynamics. The developed procedure allows also to characterize promoter macrostates in terms of thermo-statistical magnitudes (free energy and entropy), with valuable biological implications. Our results agree with independent previous experimental results. Thus, our methods appear as a powerful complementary tool for identifying protein binding sites in promoter sequences. © 2014 Tapia-Rojo et al.
Liggi S.,University of Cambridge |
Drakakis G.,University of Cambridge |
Koutsoukas A.,University of Cambridge |
Cortes-Ciriano I.,Institute Pasteur Paris |
And 12 more authors.
Future Medicinal Chemistry | Year: 2014
Background: An in silico mechanism-of-Action analysis protocol was developed, comprising molecule bioactivity profiling, annotation of predicted targets with pathways and calculation of enrichment factors to highlight targets and pathways more likely to be implicated in the studied phenotype. Results: The method was applied to a cytotoxicity phenotypic endpoint, with enriched targets/pathways found to be statistically significant when compared with 100 random datasets. Application on a smaller apoptotic set (10 molecules) did not allowed to obtain statistically relevant results, suggesting that the protocol requires modification such as analysis of the most frequently predicted targets/annotated pathways. Conclusion: Pathway annotations improved the mechanism-of-Action information gained by target prediction alone, allowing a better interpretation of the predictions and providing better mapping of targets onto pathways. © 2014 Future Science Ltd.
PubMed | University of Chile, University of Murcia, San Antonio de Murcia Catholic University and Institute for Biocomputation and Physics of Complex Systems
Type: | Journal: BioMed research international | Year: 2014
Bioinformatics is an interdisciplinary research field that develops tools for the analysis of large biological databases, and, thus, the use of high performance computing (HPC) platforms is mandatory for the generation of useful biological knowledge. The latest generation of graphics processing units (GPUs) has democratized the use of HPC as they push desktop computers to cluster-level performance. Many applications within this field have been developed to leverage these powerful and low-cost architectures. However, these applications still need to scale to larger GPU-based systems to enable remarkable advances in the fields of healthcare, drug discovery, genome research, etc. The inclusion of GPUs in HPC systems exacerbates power and temperature issues, increasing the total cost of ownership (TCO). This paper explores the benefits of volunteer computing to scale bioinformatics applications as an alternative to own large GPU-based local infrastructures. We use as a benchmark a GPU-based drug discovery application called BINDSURF that their computational requirements go beyond a single desktop machine. Volunteer computing is presented as a cheap and valid HPC system for those bioinformatics applications that need to process huge amounts of data and where the response time is not a critical factor.
Aniello P.,University of Naples Federico II |
Clemente-Gallardo J.,Institute for Biocomputation and Physics of Complex Systems |
Marmo G.,University of Naples Federico II |
Volkert G.F.,University of Naples Federico II |
Volkert G.F.,Ludwig Maximilians University of Munich
International Journal of Geometric Methods in Modern Physics | Year: 2010
The geometrical description of a Hilbert space associated with a quantum system considers a Hermitian tensor to describe the scalar inner product of vectors which are now described by vector fields. The real part of this tensor represents a flat Riemannian metric tensor while the imaginary part represents a symplectic two-form. The immersion of classical manifolds in the complex projective space associated with the Hilbert space allows to pull-back tensor fields related to previous ones, via the immersion map. This makes available, on these selected manifolds of states, methods of usual Riemannian and symplectic geometry. Here, we consider these pulled-back tensor fields when the immersed submanifold contains separable states or entangled states. Geometrical tensors are shown to encode some properties of these states. These results are not unrelated with criteria already available in the literature. We explicitly deal with some of these relations. © 2010 World Scientific Publishing Company.
PubMed | Institute for Biocomputation and Physics of Complex Systems
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2014
The flavin isoalloxazine ring in electron transferases functions in a redox capacity, being able to take up electrons from a donor to subsequently deliver them to an acceptor. The main characteristics of these flavoproteins, including their unique ability to mediate obligatory processes of two-electron transfers with those involving single-electron transfer, are here described. To illustrate the versatility of these proteins, the acquired knowledge of the function of the two electron transferases involved in the cyanobacterial photosynthetic electron transfer from photosystem I to NADP(+) is presented. Many aspects of their biochemistry and biophysics have been extensively characterized using site-directed mutagenesis, steady-state and transient kinetics, spectroscopy, calorimetry, X-ray crystallography, electron paramagnetic resonance, and computational methods.