Methods for protein complex prediction and their contributions towards understanding the organization, function and dynamics of complexes

Complexes of physically interacting proteins constitute fundamental functional units responsible for driving biological processes within cells. A faithful reconstruction of the entire set of complexes is therefore essential to understand the functional organization of cells. In this review, we discuss the key contributions of computational methods developed till date (approximately between 2003 and 2015) for identifying complexes from the network of interacting proteins (PPI network). We evaluate in depth the performance of these methods on PPI datasets from yeast, and highlight challenges faced by these methods, in particular detection of sparse and small or sub- complexes and discerning of overlapping complexes. We describe methods for integrating diverse information including expression profiles and 3D structures of proteins with PPI networks to understand the dynamics of complex formation, for instance, of time-based assembly of complex subunits and formation of fuzzy complexes from intrinsically disordered proteins. Finally, we discuss methods for identifying dysfunctional complexes in human diseases, an application that is proving invaluable to understand disease mechanisms and to discover novel therapeutic targets. We hope this review aptly commemorates a decade of research on computational prediction of complexes and constitutes a valuable reference for further advancements in this exciting area.Comment: 1 Tabl

Structural Prediction of Protein–Protein Interactions by Docking: Application to Biomedical Problems

A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.Spanish Ministry of Economy grant number BIO2016-79960-R; D.B.B. is supported by a predoctoral fellowship from CONACyT; M.R. is supported by an FPI fellowship from the Severo Ochoa program. We are grateful to the Joint BSC-CRG-IRB Programme in Computational Biology.Peer ReviewedPostprint (author's final draft

Digital Ecosystems: Ecosystem-Oriented Architectures

We view Digital Ecosystems to be the digital counterparts of biological ecosystems. Here, we are concerned with the creation of these Digital Ecosystems, exploiting the self-organising properties of biological ecosystems to evolve high-level software applications. Therefore, we created the Digital Ecosystem, a novel optimisation technique inspired by biological ecosystems, where the optimisation works at two levels: a first optimisation, migration of agents which are distributed in a decentralised peer-to-peer network, operating continuously in time; this process feeds a second optimisation based on evolutionary computing that operates locally on single peers and is aimed at finding solutions to satisfy locally relevant constraints. The Digital Ecosystem was then measured experimentally through simulations, with measures originating from theoretical ecology, evaluating its likeness to biological ecosystems. This included its responsiveness to requests for applications from the user base, as a measure of the ecological succession (ecosystem maturity). Overall, we have advanced the understanding of Digital Ecosystems, creating Ecosystem-Oriented Architectures where the word ecosystem is more than just a metaphor.Comment: 39 pages, 26 figures, journa

Predicting Landscape-Genetic Consequences of Habitat Loss, Fragmentation and Mobility for Multiple Species of Woodland Birds

Inference concerning the impact of habitat fragmentation on dispersal and gene flow is a key theme in landscape genetics. Recently, the ability of established approaches to identify reliably the differential effects of landscape structure (e.g. land-cover composition, remnant vegetation configuration and extent) on the mobility of organisms has been questioned. More explicit methods of predicting and testing for such effects must move beyond post hoc explanations for single landscapes and species. Here, we document a process for making a priori predictions, using existing spatial and ecological data and expert opinion, of the effects of landscape structure on genetic structure of multiple species across replicated landscape blocks. We compare the results of two common methods for estimating the influence of landscape structure on effective distance: least-cost path analysis and isolation-by-resistance. We present a series of alternative models of genetic connectivity in the study area, represented by different landscape resistance surfaces for calculating effective distance, and identify appropriate null models. The process is applied to ten species of sympatric woodland-dependant birds. For each species, we rank a priori the expectation of fit of genetic response to the models according to the expected response of birds to loss of structural connectivity and landscape-scale tree-cover. These rankings (our hypotheses) are presented for testing with empirical genetic data in a subsequent contribution. We propose that this replicated landscape, multi-species approach offers a robust method for identifying the likely effects of landscape fragmentation on dispersal

Predictive Analytics Lead to Smarter Self-Organizing Directional Wireless Backbone Networks

Directional wireless systems are becoming a cost-effective approach towards providing a high-speed, reliable, broadband connection for the ubiquitous mobile wireless devices in use today. The most common of these systems consists of narrow-beam radio frequency (RF) and free-space-optical (FSO) links, which offer speeds between 100Mbps and 100Gbps while offering bit-error-rates comparable to fixed fiber optic installations. In addition, spatial and spectral efficiencies are accessible with directional wireless systems that cannot be matched with broadcast systems. The added benefits of compact designs permit the installation of directional antennas on-board unmanned autonomous systems (UAS) to provide network availability to regions prone to natural disasters, in maritime situations, and in war-torn countries that lack infrastructure security. In addition, through the use of intelligent network-centric algorithms, a flexible airborne backbone network can be established to dodge the scalability limitations of traditional omnidirectional wireless networks. Assuring end-to-end connectivity and coverage is the main challenge in the design of directional wireless backbone (DWB) networks. Conflating the duality of these objectives with the dynamical nature of the environment in which DWB networks are deployed, in addition to the standardized network metrics such as latency-minimization and throughput maximization, demands a rigorous control process that encompasses all aspects of the system. This includes the mechanical steering of the directional point-to-point link and the monitoring of aggregate network performance (e.g. dropped packets). The inclusion of processes for topology control, mobility management, pointing, acquisition, and tracking of the directional antennas, alongside traditional protocols (e.g. IPv6) provides a rigorous framework for next-generation mobile directional communication networks. This dissertation provides a novel approach to increase reliability in reconfigurable beam-steered directional wireless backbone networks by predicating optimal network reconfigurations wherein the network is modeled as a giant molecule in which the point-to-point links between two UASs are able to grow and retract analogously to the bonds between atoms in a molecule. This cross-disciplinary methodology explores the application of potential energy surfaces and normal mode analysis as an extension to the topology control optimization. Each of these methodologies provides a new and unique ability for predicting unstable configurations of DWB networks through an understanding of second-order principle dynamics inherent within the aggregate configuration of the system. This insight is not available through monitoring individual link performance. Together, the techniques used to model the DWB network through molecular dynamics are referred to as predictive analytics and provide reliable results that lead to smarter self-organizing reconfigurable beam-steered DWB networks. Furthermore, a comprehensive control architecture is proposed that complements traditional network science (e.g. Internet protocol) and the unique design aspects of DWB networks. The distinct ability of a beam-steered DWB network to adjust the direction of its antennas (i.e. reconfigure) in response to degraded effects within the atmosphere or due to an increased separation of nodes, is not incorporated in traditional network processes such re-routing mechanism, and therefore, processes for reconfiguration can be abstracted which both optimize the physical interconnections while maintaining interoperability with existing protocols. This control framework is validated using network metrics for latency and throughput and compared to existing architectures which use only standard re-routing mechanisms. Results are shown that validate both the analogous molecular modeling of a reconfigurable beam-steered directional wireless backbone network and a comprehensive control architecture which coalesces the unique capabilities of reconfiguration and mobility of mobile wireless backbone networks with existing protocols for networks such as IPv6