Pairwise Contacts Research Articles

Mapping the spectrum of 3D communities in human chromosome conformation capture data

Several experiments show that the three dimensional (3D) organization of chromosomes affects genetic processes such as transcription and gene regulation. To better understand this connection, researchers developed the Hi-C method that is able to detect the pairwise physical contacts of all chromosomal loci. The Hi-C data show that chromosomes are composed of 3D compartments that range over a variety of scales. However, it is challenging to systematically detect these cross-scale structures. Most studies have therefore designed methods for specific scales to study foremost topologically associated domains (TADs) and A/B compartments. To go beyond this limitation, we tailor a network community detection method that finds communities in compact fractal globule polymer systems. Our method allows us to continuously scan through all scales with a single resolution parameter. We found: (i) polymer segments belonging to the same 3D community do not have to be in consecutive order along the polymer chain. In other words, several TADs may belong to the same 3D community. (ii) CTCF proteins—a loop-stabilizing protein that is ascribed a big role in TAD formation—are well correlated with community borders only at one level of organization. (iii) TADs and A/B compartments are traditionally treated as two weakly related 3D structures and detected with different algorithms. With our method, we detect both by simply adjusting the resolution parameter. We therefore argue that they represent two specific levels of a continuous spectrum 3D communities, rather than seeing them as different structural entities.

Proactively Placing Static Relays With Social-Link Awareness in Mobile Social Networks

Mobile social networks have been exploited for data forwarding due to its low cost and better robustness. Existing data forwarding strategies in mobile social networks rely on the pairwise contacts among mobile users. However, these pairwise contacts only provide limited forwarding capabilities and most data fail to be delivered before the expiration time. In this paper, we improve the performance of data forwarding by proactively placing low-cost static relays to increase the opportunistic contacts among the mobile nodes. Based on this idea, an important question is where to place the static relays in the network to best facilitate data forwarding among nodes. To answer this question, we first analyze four real-world datasets of mobile social networks, and identify that data forwarding only appears in a small group of social links. Then, we formalize the problem of static relay placement as an optimization problem, and propose a heuristic based solution to improve the data forwarding performance along these social links. Considering the fact that the social links may evolve over time, we also propose an efficient relay replacement algorithm which replaces the outdated relays with new relays to further improve the data forwarding performance. Evaluation results show that the proposed relay based solutions can significantly improve the performance of data forwarding in mobile social networks.

Multiplex chromatin interactions with single-molecule precision.

The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus1. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)2, and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)3, have revealed topologically associating domains4 with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription5-7. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C8 potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis9 but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription.

Statistical investigations of protein residue direct couplings.

Protein Direct Coupling Analysis (DCA), which predicts residue-residue contacts based on covarying positions within a multiple sequence alignment, has been remarkably effective. This suggests that there is more to learn from sequence correlations than is generally assumed, and calls for deeper investigations into DCA and perhaps into other types of correlations. Here we describe an approach that enables such investigations by measuring, as an estimated p-value, the statistical significance of the association between residue-residue covariance and structural interactions, either internal or homodimeric. Its application to thirty protein superfamilies confirms that direct coupling (DC) scores correlate with 3D pairwise contacts with very high significance. This method also permits quantitative assessment of the relative performance of alternative DCA methods, and of the degree to which they detect direct versus indirect couplings. We illustrate its use to assess, for a given protein, the biological relevance of alternative conformational states, to investigate the possible mechanistic implications of differences between these states, and to characterize subtle aspects of direct couplings. Our analysis indicates that direct pairwise correlations may be largely distinct from correlated patterns associated with functional specialization, and that the joint analysis of both types of correlations can yield greater power. Data, programs, and source code are freely available at http://evaldca.igs.umaryland.edu.

Service Provisioning in Mobile Environments through Opportunistic Computing

Opportunistic computing is a paradigm for completely self-organised pervasive networks. Instead of relying only on fixed infrastructures as the cloud, users' devices act as service providers for each other. They use pairwise contacts to collect information about services provided and amount of time to provide them by the encountered nodes. At each node, upon generation of a service request, this information is used to choose the most efficient service, or composition of services, that satisfy that request, based on local knowledge. Opportunistic computing can be exploited in several scenarios, including mobile social networks, IoT and Internet 4.0. In this paper we propose an opportunistic computing algorithm based on an analytical model, which ranks the available (composition of) services, based on their expected completion time. Through the model, a service requesters picks the one that is expected to be the best. Experiments show that the algorithm is accurate in ranking services, thus providing an effective service-selection policy. Such a policy achieves significantly lower service provisioning times compared to other reference policies. Its performance is tested in a wide range of scenarios varying the nodes mobility, the size of input/output parameters, the level of resource congestion, the computational complexity of service executions.

Enhancer hubs and loop collisions identified from single-allele topologies.

Chromatin folding contributes to the regulation of genomic processes such as gene activity. Existing conformation capture methods characterize genome topology through analysis of pairwise chromatin contacts in populations of cells but cannot discern whether individual interactions occur simultaneously or competitively. Here we present multi-contact 4C (MC-4C), which applies Nanopore sequencing to study multi-way DNA conformations of individual alleles. MC-4C distinguishes cooperative from random and competing interactions and identifies previously missed structures in subpopulations of cells. We show that individual elements of the β-globin superenhancer can aggregate into an enhancer hub that can simultaneously accommodate two genes. Neighboring chromatin domain loops can form rosette-like structures through collision of their CTCF-bound anchors, as seen most prominently in cells lacking the cohesin-unloading factor WAPL. Here, massive collision of CTCF-anchored chromatin loops is believed to reflect 'cohesin traffic jams'. Single-allele topology studies thus help us understand the mechanisms underlying genome folding and functioning.

Recurring Contacts between Groups of Devices: Analysis and Application

The capability to anticipate a contact with another device can contribute to improving the performance and user satisfaction of mobile social network applications and of any other relying on some form of data harvesting or hoarding. This paper presents a nine year data set of wireless access logs produced by more than 70,000 devices and 40,000 users. Research on the recurring contact patterns observed between groups of devices permitted to model the probabilities of occurrence of a contact at a predefined date between pairs of devices. As an example, the paper presents and evaluates an algorithm that provides daily contact predictions, based on the history of past pairwise contacts and its application on a reputation service.

Assessing the Structural Basis of μ-Conotoxin KIIIA Inhibition of the Voltage-Gated Sodium Channel Nav1.7

The voltage-gated sodium channel subtype Nav1.7 has been shown to play a critical role in pain signaling, making it an important drug target. A number of peptide toxins from cone snails (conotoxins) inhibit sodium conduction through Nav1.7 with high affinity, and make potential scaffolds for selective channel inhibitors. However, the atomistic details of protein-protein interactions between conotoxins and Nav channels necessary for rational design of such inhibitors remain unclear. Our study aims to further define the molecular determinants of μ-conotoxin KIIIA action against the human Nav1.7 channel (hNav1.7). We have previously used Rosetta computational modeling software to generate preliminary molecular models of the hNav1.7 pore-forming domain based on the NavAb crystal structure (PDB ID: 3RVY). To capitalize on recent advances, we have updated our hNav1.7 homology model using the recent cryo-EM structure of the electric eel Nav1.4 channel (PDB ID: 5XSY) as a template. To test predicted pairwise contacts between toxin and channel, point mutations of hNav1.7 and conotoxin KIIIA in the putative binding site have been generated. We have identified several residues that alter the kinetics of toxin binding, notably acidic residues on the DII pore-helix. Our experimental and modeling results may be useful for rational design of novel peptides to inhibit hNav1.7 with high affinity and selectivity.

Influenza Binding Avidity Governed by Sterol-Dependent Ganglioside Dynamics

Influenza virions attach to host membranes by binding cell-surface glycans containing sialic acid, initiating the viral life cycle and infecting cells. While the primary determinant of viral binding is thought to be the glycan chemical structure, single interactions between a viral hemagglutinin binding site and a sialic acid are weak, so binding specificity is presumed to occur via multivalent interactions. Here, we show that target membrane composition can alter influenza binding while total receptor content is held constant. We hypothesize that this effect occurs by changing the spatial distribution of target receptors. Viral binding was quantitated by monitoring individual viruses binding to synthetic supported lipid bilayers using fluorescence microscopy. Adding cholesterol to target bilayers increased binding in a dose-dependent manner. Furthermore, membranes containing 5-cholesten-3-one, an oxidized variant of cholesterol, displayed significantly higher binding avidity compared to membranes supplemented with an equal amount of cholesterol. When sterol mole fractions were held constant, viral target receptor concentration and binding exhibited a sigmoidal relationship, confirming the multivalent nature of virus receptor binding. The cooperativity required for binding established the potential for local receptor concentration to regulate membrane binding affinity. To develop a physical model for sterol-induced changes in the lateral organization of GD1a receptors, we performed coarse grained molecular dynamics simulations of target lipid bilayers. Irrespective of sterol content, GD1a receptors showed strong tendencies to self-associate. The inclusion of cholesterol in membranes increased pairwise receptor contacts, suggesting that sterol addition stabilized target receptor clustering. This observation supports the hypothesis that sterols can modulate membrane nanoscale organization and thus alter viral binding avidity, illuminating a previously underappreciated mechanism by which target membrane context can influence influenza infectivity.

Capturing pairwise and multi-way chromosomal conformations using chromosomal walks.

Chromosomes are folded into highly compacted structures to accommodate physical constraints within nuclei and to regulate access to genomic information. Recently, global mapping of pairwise contacts showed that loops anchoring topological domains (TADs) are highly conserved between cell types and species. Whether pairwise loops synergize to form higher-order structures is still unclear. Here we develop a conformation capture assay to study higher-order organization using chromosomal walks (C-walks) that link multiple genomic loci together into proximity chains in human and mouse cells. This approach captures chromosomal structure at varying scales. Inter-chromosomal contacts constitute only 7-10% of the pairs and are restricted by interfacing TADs. About half of the C-walks stay within one chromosome, and almost half of those are restricted to intra-TAD spaces. C-walks that couple 2-4 TADs indicate stochastic associations between transcriptionally active, early replicating loci. Targeted analysis of thousands of 3-walks anchored at highly expressed genes support pairwise, rather than hub-like, chromosomal topology at active loci. Polycomb-repressed Hox domains are shown by the same approach to enrich for synergistic hubs. Together, the data indicate that chromosomal territories, TADs, and intra-TAD loops are primarily driven by nested, possibly dynamic, pairwise contacts.

Efficiency of the induction of cytomixis in the microsporogenesis of dicotyledonous (N. tabacum L.) and monocotyledonous (H. distichum L.) plants by thermal stress

The efficiencies of the induction of cytomixis in microsporogenesis by thermal stress are compared in tobacco (N. tabacum L.) and barley (H. distichum L.) It has been shown that different thermal treatment schedules (budding tobacco plants at 50°C and air-dried barley grains at 48°C) produce similar results in the species: the frequency of cytomixis increases, and its maximum shifts to later stages of meiosis. However, the species show differences in response. The cytomixis frequency increase in tobacco is more pronounced, and its maximum shifts from the zygotene–pachytene stages of meiotic prophase I to prometaphase–metaphase I. Later in the meiosis, aberrations in chromosome structure and meiotic apparatus formation typical of cytomixis are noted, as well as cytomixis activation in tapetum cells. Thermal stress disturbs the integration of callose- bearing vesicles into the callose wall. Cold treatment at 7°C does not affect cytomixis frequency in tobacco microsporogenesis. Incubation of barley seeds at 48°C activates cytomixis in comparison to the control, shifts its maximum from the premeiotic interphase to zygotene, and changes the habit of cytomictic interactions from pairwise contacts to the formation of multicellular clusters. Thermal treatment induces cytomictic interactions within the tapetum and between microsporocytes and the tapetum. However, later meiotic phases show no adverse consequences of active cytomixis in barley. It is conjectured that heat stress affects callose metabolism and integration into the forming callose wall, thereby causing incomplete closure of cytomictic channels and favoring intercellular chromosome migration at advanced meiotic stages.

Distributed Workload Dissemination for Makespan Minimization in Disruption Tolerant Networks

Mobile devices are undergoing explosive proliferation today. Although they are gaining more and more capabilities, they still fall short to execute complex applications. One possible solution to alleviate this limitation is offloading tasks to remote clouds. However, it may require persistent connectivity to the Internet and thus is not always available or affordable. An alternative solution is taking advantage of pervasive mobile devices and their pairwise encounters. In this paradigm, complex tasks from mobile devices are processed in a distributed and collaborative fashion on all mobile devices that are loosely-connected. Working towards this vision, this paper studies the following problem: given a task that originates at some node in a Disruption Tolerant Network (DTN), how are we to disseminate the task's workload during the pairwise contacts among mobile devices to achieve makespan minimization? We first imagine access to an oracle that has global and future knowledge of node mobility, and we design a provably-optimal centralized polynomial-time solution as the benchmark for comparison. With the insights obtained from the centralized solution, we then develop a distributed dissemination algorithm, $\mathsf{D2}$ , which maintains certain neighborhood information at individual nodes. $\mathsf{D2}$ makes dissemination decisions based on the estimations of the potential computational capacities and the future workloads of mobile nodes. Extensive trace-driven simulations confirm the effectiveness of $\mathsf{D2}$ .

Spatial Heat Maps from Fast Information Matching of Fast and Slow Degrees of Freedom: Application to Molecular Dynamics Simulations.

We introduce a fast information matching (FIM) method for transforming time domain data into spatial images through handshaking between fast and slow degrees of freedom. The analytics takes advantage of the detailed time series available from biomolecular computer simulations, and it yields spatial heat maps that can be visualized on 3D molecular structures or in the form of interaction networks. The speed of our efficient mutual information solver is on the order of a basic Pearson cross-correlation calculation. We demonstrate that the FIM method is superior to linear cross-correlation for the detection of nonlinear dependence in challenging situations where measures for the global dynamics (the "activity") diverge. The analytics is applied to the detection of hinge-bending hot spots and to the prediction of pairwise contacts between residues that are relevant for the global activity exhibited by the molecular dynamics (MD) trajectories. Application examples from various MD laboratories include the millisecond bovine pancreatic trypsin inhibitor (BPTI) trajectory using canonical MD, a Gaussian accelerated MD folding trajectory of chignolin, and the heat-induced unfolding of engrailed homeodomain (EnHD). The FIM implementation will be freely disseminated with our open-source package, TimeScapes.

Remotely Piloted Aircraft Systems and a Wireless Sensors Network for Radiological Accidents

In critical radiological situations, the real time information that we could get from the disaster area becomes of great importance. However, communication systems could be affected after a radiological accident. The proposed network in this research consists of distributed sensors in charge of collecting radiological data and ground vehicles that are sent to the nuclear plant at the moment of the accident to sense environmental and radiological information. Afterwards, data would be analyzed in the control center. Collected data by sensors and ground vehicles would be delivered to a control center using Remotely Piloted Aircraft Systems (RPAS) as a message carrier. We analyze the pairwise contacts, as well as visiting times, data collection, capacity of the links, size of the transmission window of the sensors, and so forth. All this calculus was made analytically and compared via network simulations.

Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a.

The spider-venom peptide PcTx1 is the most potent and selective inhibitor of acid-sensing ion channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interaction should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β-hairpin loop; conclusions confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : channel contacts were observed in these crystal structures, but it remains unclear which of these are functionally important. We combined molecular dynamics (MD) simulations of the PcTx1 : cASIC1 complex with mutagenesis of PcTx1 and rat ASIC1a. Crystal structures of the PcTx1 : cASIC1 complex indicated that 15 PcTx1 residues form a total of 57 pairwise intermolecular contacts (<5 Å) with 32 channel residues. MD simulations, however, suggested that about half of these interactions do not persist in solution. Mutation to alanine of only eight of 15 PcTx1 contact residues substantially altered ASIC1a inhibition by PcTx1. Our data reveal that many of the peptide-channel interactions observed in the PcTx1 : cASIC1 crystal structures are not important for PcTx1 inhibition of rat ASIC1a. We identified the atomic interactions that are critical for PcTx1 inhibition of ASIC1a. Our data highlight the value of combining structural information, MD and functional experiments to obtain detailed insight into the molecular basis of protein : protein interactions.

Identifying multi-locus chromatin contacts in human cells using tethered multiple 3C

BackgroundSeveral recently developed experimental methods, each an extension of the chromatin conformation capture (3C) assay, have enabled the genome-wide profiling of chromatin contacts between pairs of genomic loci in 3D. Especially in complex eukaryotes, data generated by these methods, coupled with other genome-wide datasets, demonstrated that non-random chromatin folding correlates strongly with cellular processes such as gene expression and DNA replication.ResultsWe describe a genome architecture assay, tethered multiple 3C (TM3C), that maps genome-wide chromatin contacts via a simple protocol of restriction enzyme digestion and religation of fragments upon agarose gel beads followed by paired-end sequencing. In addition to identifying contacts between pairs of loci, TM3C enables identification of contacts among more than two loci simultaneously. We use TM3C to assay the genome architectures of two human cell lines: KBM7, a near-haploid chronic leukemia cell line, and NHEK, a normal diploid human epidermal keratinocyte cell line. We confirm that the contact frequency maps produced by TM3C exhibit features characteristic of existing genome architecture datasets, including the expected scaling of contact probabilities with genomic distance, megabase scale chromosomal compartments and sub-megabase scale topological domains. We also confirm that TM3C captures several known cell type-specific contacts, ploidy shifts and translocations, such as Philadelphia chromosome formation (Ph+) in KBM7. We confirm a subset of the triple contacts involving the IGF2-H19 imprinting control region (ICR) using PCR analysis for KBM7 cells. Our genome-wide analysis of pairwise and triple contacts demonstrates their preference for linking open chromatin regions to each other and for linking regions with higher numbers of DNase hypersensitive sites (DHSs) to each other. For near-haploid KBM7 cells, we infer whole genome 3D models that exhibit clustering of small chromosomes with each other and large chromosomes with each other, consistent with previous studies of the genome architectures of other human cell lines.ConclusionTM3C is a simple protocol for ascertaining genome architecture and can be used to identify simultaneous contacts among three or four loci. Application of TM3C to a near-haploid human cell line revealed large-scale features of chromosomal organization and multi-way chromatin contacts that preferentially link regions of open chromatin.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1236-7) contains supplementary material, which is available to authorized users.

Finite-Size Conformational Transitions: A Unifying Concept Underlying Chromosome Dynamics

Investigating average thermodynamic quantities is not sufficient to understand conformational transitions of a finite-size polymer. We propose that such transitions are better described in terms of the probability distribution of some finite-size order parameter, and the evolution of this distribution as a control parameter varies. We demonstrate this claim for the coil-globule transition of a linear polymer and its mapping onto a two-state model. In a biological context, polymer models delineate the physical constraints experienced by the genome at different levels of organization, from DNA to chromatin to chromosome. We apply our finite-size approach to the formation of plectonemes in a DNA segment submitted to an applied torque and the ensuing helix-coil transition that can be numerically observed, with a coexistence of the helix and coil states in a range of parameters. Polymer models are also essential to analyze recent in vivo experiments providing the frequency of pairwise contacts between genomic loci. The probability distribution of these contacts yields quantitative information on the conformational fluctuations of chromosome regions. The changes observed in the shape of the distribution when the cell type or the physiological conditions vary may reveal an epigenetic modulation of the conformational constraints experienced by the chromosomes.

Folding similarity of the outer pore region in prokaryotic and eukaryotic sodium channels revealed by docking of conotoxins GIIIA, PIIIA, and KIIIA in a NavAb-based model of Nav1.4.

Voltage-gated sodium channels are targets for many drugs and toxins. However, the rational design of medically relevant channel modulators is hampered by the lack of x-ray structures of eukaryotic channels. Here, we used a homology model based on the x-ray structure of the NavAb prokaryotic sodium channel together with published experimental data to analyze interactions of the μ-conotoxins GIIIA, PIIIA, and KIIIA with the Nav1.4 eukaryotic channel. Using Monte Carlo energy minimizations and published experimentally defined pairwise contacts as distance constraints, we developed a model in which specific contacts between GIIIA and Nav1.4 were readily reproduced without deformation of the channel or toxin backbones. Computed energies of specific interactions between individual residues of GIIIA and the channel correlated with experimental estimates. The predicted complexes of PIIIA and KIIIA with Nav1.4 are consistent with a large body of experimental data. In particular, a model of Nav1.4 interactions with KIIIA and tetrodotoxin (TTX) indicated that TTX can pass between Nav1.4 and channel-bound KIIIA to reach its binding site at the selectivity filter. Our models also allowed us to explain experimental data that currently lack structural interpretations. For instance, consistent with the incomplete block observed with KIIIA and some GIIIA and PIIIA mutants, our computations predict an uninterrupted pathway for sodium ions between the extracellular space and the selectivity filter if at least one of the four outer carboxylates is not bound to the toxin. We found a good correlation between computational and experimental data on complete and incomplete channel block by native and mutant toxins. Thus, our study suggests similar folding of the outer pore region in eukaryotic and prokaryotic sodium channels.

Identifying Key Amino Acid Residues That Affect α-Conotoxin AuIB Inhibition of α3β4 Nicotinic Acetylcholine Receptors

α-Conotoxin AuIB is a selective α3β4 nicotinic acetylcholine receptor (nAChR) subtype inhibitor. Its analgesic properties are believed to result from it activating GABAB receptors and subsequently inhibiting CaV2.2 voltage-gated calcium channels. The structural determinants that mediate diverging AuIB activity at these targets are unknown. We performed alanine scanning mutagenesis of AuIB and α3β4 nAChR, homology modeling, and molecular dynamics simulations to identify the structural determinants of the AuIB·α3β4 nAChR interaction. Two alanine-substituted AuIB analogues, [P6A]AuIB and [F9A]AuIB, did not inhibit the α3β4 nAChR. NMR and CD spectroscopy studies demonstrated that [F9A]AuIB retains its native globular structure, so its activity loss is probably due to loss of specific toxin-receptor residue pairwise contacts. Compared with AuIB, the concentration-response curve for inhibition of α3β4 by [F9A]AuIB shifted rightward more than 10-fold, and its subtype selectivity profile changed. Homology modeling and molecular dynamics simulations suggest that Phe-9 of AuIB interacts with a two-residue binding pocket on the β4 nAChR subunit. This hypothesis was confirmed by site-directed mutagenesis of the β4-Trp-59 and β4-Lys-61 residues of loop D, which form a putative binding pocket. AuIB analogues with Phe-9 substitutions corroborated the finding of a binding pocket on the β4 subunit and gave further insight into how AuIB Phe-9 interacts with the β4 subunit. In summary, we identified critical residues that mediate interactions between AuIB and its cognate nAChR subtype. These findings might help improve the design of analgesic conopeptides that selectively "avoid" nAChR receptors while targeting receptors involved with nociception.

DockTrina: Docking triangular protein trimers

In spite of the abundance of oligomeric proteins within a cell, the structural characterization of protein-protein interactions is still a challenging task. In particular, many of these interactions involve heteromeric complexes, which are relatively difficult to determine experimentally. Hence there is growing interest in using computational techniques to model such complexes. However, assembling large heteromeric complexes computationally is a highly combinatorial problem. Nonetheless the problem can be simplified greatly by considering interactions between protein trimers. After dimers and monomers, triangular trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) are the most frequently observed quaternary structural motifs according to the three-dimensional (3D) complex database. This article presents DockTrina, a novel protein docking method for modeling the 3D structures of nonsymmetrical triangular trimers. The method takes as input pair-wise contact predictions from a rigid body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation test. Finally, it ranks the predictions using a scoring function which combines triples of pair-wise contact terms and a geometric clash penalty term. The overall approach takes less than 2 min per complex on a modern desktop computer. The method is tested and validated using a benchmark set of 220 bound and seven unbound protein trimer structures. DockTrina will be made available at http://nano-d.inrialpes.fr/software/docktrina.