Favorable Contacts Research Articles

Primary Sequence Controls the Specificity and Affinity of a Small Molecule Binding to the Intrinsically Disordered Protein c-Myc

Intrinsically disordered proteins (IDPs) are characterized by high flexibility and low hydrophobic to charged residue ratio. The transcription factor c-Myc is an IDP deregulated in many forms of cancer. The protein undergoes coupled folding and binding with its obligate dimerization partner Max, which is also a disordered monomer, to form a basic helix-loop-helix leucine zipper (bHLHZip). A small molecule, 10058-F4, binds specifically within an 11 amino acid region of the bHLHZip of c-Myc, stabilizing the disordered monomer. The affinity determining residues of the 10058-F4 binding site on c-Myc were distinguished by mutating individual residues to alanine and subsequently measuring binding of 10058-F4. Mutation of both hydrophobic and certain hydrophilic residues attenuated binding of the small molecule to c-Myc. The affinity determining residues may affect binding through direct, energetically favorable contact with the small molecule or via a conformational influence on the IDP which favors binding. Within the proteome (SLiMSearch3), only two proteins are identified with five affinity determining residues. Six affinity determining residues are enough to specify c-Myc. A minimal set of these key residues were introduced into Max, which does not normally interact with 10058-F4. The novel protein, ModMax, binds 10058-F4. Although the alanine scan distinguished the necessary amino acids for binding, conservative mutations of some affinity determining residues demonstrated that 10058-F4 affinity is tunable. Upon substitution of Y to W, the affinity was improved by an order of magnitude. On the other hand, the affinity decreased five-fold upon substitution of E to N. Primary sequence alone, without extended secondary and tertiary structure, is sufficient to confer both specificity and affinity of a small molecule-IDP interaction.

Genetics of critical contacts and clashes in the DNA packaging specificities of bacteriophages λ and 21

The cos sites in λ and 21 chromosomes contain binding sites that recruit terminase to initiate DNA packaging. The small subunits of terminase, gpNu1 (λ) and gp1 (21), have winged helix-turn-helix DNA binding domains, where the recognition helixes differ in four of nine residues. To initiate packaging, the small subunit binds three R sequences in the cosB subsite. λ and 21 cannot package each other׳s DNA, due to recognition helix and R sequence differences. In λ and 21 cosBs, two bp, tri1 and tri2, are conserved in the R sequences yet differ between the phages; they are proposed to play a role in phage-specific packaging by λ and 21. Genetic experiments done with mixed and matched terminase and cosB alleles show packaging specificity depends on favorable contacts and clashes. These interactions indicate that the recognition helixes orient with residues 20 and 24 proximal to tri2 and tri1, respectively.

Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias.

Human ryanodine receptor 2 (hRyR2) mediates calcium release from the sarcoplasmic reticulum, enabling cardiomyocyte contraction. The N-terminal region of hRyR2 (amino acids 1-606) is the target of >30 arrhythmogenic mutations and contains a binding site for phosphoprotein phosphatase 1. Here, the solution and crystal structures determined under near-physiological conditions, as well as a homology model of the hRyR2 N-terminal region, are presented. The N-terminus is held together by a unique network of interactions among its three domains, A, B and C, in which the central helix (amino acids 410-437) plays a prominent stabilizing role. Importantly, the anion-binding site reported for the mouse RyR2 N-terminal region is notably absent from the human RyR2. The structure concurs with the differential stability of arrhythmogenic mutations in the central helix (R420W, I419F and I419F/R420W) which are owing to disparities in the propensity of mutated residues to form energetically favourable or unfavourable contacts. In solution, the N-terminus adopts a globular shape with a prominent tail that is likely to involve residues 545-606, which are unresolved in the crystal structure. Docking the N-terminal domains into cryo-electron microscopy maps of the closed and open RyR1 conformations reveals C(α) atom movements of up to 8 Å upon channel gating, and predicts the location of the leucine-isoleucine zipper segment and the interaction site for spinophilin and phosphoprotein phosphatase 1 on the RyR surface.

Exploring the influence of the protein environment on metal-binding pharmacophores.

The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a “chelator”. The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.

Studies of Metal Dichalcogenide Formation Using Electrochemical ALD

Group VI transition metal dichalcogenides (TMDCs) are graphene-like 2D layered semiconductors that exhibit anisotropic conductivity, which favors conductivity along the basal planes.1 In particular, MoS2, MoSe2 and WSe2 have received special interests for their potential toward photoelectrochemical and photoelectronic applications. These materials have been shown to be viable hydrogen evolution reaction (HER) catalysts in photoelectrochemical water-splitting devices.1-2 Applications in solar energy conversion are feasible due to the direct band gaps these materials possess, which have energies range from near-IR to visible. They are also highly stable against photocorrosion due to the d-d transition that occur upon photoexcitation.3 Among the TMDCs, MoSe2 synthesis and characterization is currently the main focus in this group. In photovoltaic (PV) devices that commonly use Mo as the back contact, having MoSe2 as the intermediate layer between the PV absorber and the Mo back contact may create a more favorable ohmic-type contact that reduces resistive losses.4 A lower resistivity ohmic contact helps to reduce carrier recombination and improves conversion efficiency of a PV device.Formation of MoSe2 nanofilms by electrochemical atomic layer deposition (E-ALD) is currently being investigated by this group. E-ALD can be used to grow high quality nanofilms by alternating precursor solutions through a flow cell to deposit the desired elements up to one atomic layer at a time. Such fine control is possible by utilizing the underpotential deposition (UPD) of elements on each other. Pure Mo electrodeposition is hampered by the presence of HER, but “induced co-deposition” is possible by electrodepositing Mo in the presence of other metal ions.5 In E-ALD of MoSe2, UPD Se plays the role of this other metal ion. Electrochemical studies for growing MoSe2 by E-ALD as well as characterization of preliminary MoSe2 films will be presented.1. Tang, H.; Dou, K. P.; Kaun, C. C.; Kuang, Q.; Yang, S. H., MoSe2 nanosheets and their graphene hybrids: synthesis, characterization and hydrogen evolution reaction studies. J Mater Chem A 2014, 2 (2), 360-364.2. (a) Velazquez, J. M.; Saadi, F. H.; Pieterick, A. P.; Spurgeon, J. M.; Soriaga, M. P.; Brunschwig, B. S.; Lewis, N. S., Synthesis and hydrogen-evolution activity of tungsten selenide thin films deposited on tungsten foils. J Electroanal Chem 2014, 716 (0), 45-48; (b) Jaramillo, T. F.; Jorgensen, K. P.; Bonde, J.; Nielsen, J. H.; Horch, S.; Chorkendorff, I., Identification of active edge sites for electrochemical H-2 evolution from MoS2 nanocatalysts. Science 2007, 317 (5834), 100-102.3. Pathak, V. M.; Patel, K. D.; Pathak, R. J.; Srivastava, R., Improved photoconversion from MoSe2 based PEC solar cells. Sol Energ Mat Sol C 2002, 73 (2), 117-123.4. Wada, T.; Kohara, N.; Nishiwaki, S.; Negami, T., Characterization of the Cu(In,Ga)Se-2/Mo interface in CIGS solar cells. Thin Solid Films 2001, 387 (1-2), 118-122.5. (a) Chandra, S.; Sahu, S. N., Electrodeposited semiconducting molybdenum selenide films. I. Preparatory technique and structural characterisation. Journal of Physics D: Applied Physics 1984, 17 (10), 2115; (b) Delphine, S. M.; Jayachandran, M.; Sanjeeviraja, C., Pulsed electrodeposition and characterization of molybdenum diselenide thin film. Mater Res Bull 2005, 40 (1), 135-147.

Membrane interaction of bound ligands contributes to the negative binding cooperativity of the EGF receptor.

The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding measurements are consistent with a negatively cooperative model in which the ligand-binding affinity at either binding site in an EGFR dimer is weaker when the other site is occupied by a ligand. This cooperativity is widely believed to be central to the effects of ligand concentration on EGFR-mediated intracellular signaling. Although the extracellular portion of the human EGFR dimer has been resolved crystallographically, the crystal structures do not reveal the structural origin of this negative cooperativity, which has remained unclear. Here we report the results of molecular dynamics simulations suggesting that asymmetrical interactions of the two binding sites with the membrane may be responsible (perhaps along with other factors) for this negative cooperativity. In particular, in our simulations the extracellular domains of an EGFR dimer spontaneously lay down on the membrane in an orientation in which favorable membrane contacts were made with one of the bound ligands, but could not be made with the other. Similar interactions were observed when EGFR was glycosylated, as it is in vivo.

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket

Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50=0.005 μM and EC50=0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.

Explaining the Non-Newtonian Character of Aggregating Monoclonal Antibody Solutions Using Small-Angle Neutron Scattering

A monoclonal antibody solution displays an increase in low shear rate viscosity upon aggregation after prolonged incubation at 40°C. The morphology and interactions leading to the formation of the aggregates responsible for this non-Newtonian character are resolved using small-angle neutron scattering. Our data show a weak repulsive barrier before proteins aggregate reversibly, unless a favorable contact with high binding energy occurs. Two types of aggregates were identified after incubation at 40°C: oligomers with radius of gyration ∼10 nm and fractal submicrometer particles formed by a slow reaction-limited aggregation process, consistent with monomers colliding many times before finding a favorable strong interaction site. Before incubation, these antibody solutions are Newtonian liquids with no increase in low shear rate viscosity and no upturn in scattering at low wavevector, whereas aggregated solutions under the same conditions have both of these features. These results demonstrate that fractal submicrometer particles are responsible for the increase in low shear rate viscosity and low wavevector upturn in scattered intensity of aggregated antibody solutions; both are removed from aggregated samples by filtering.

Polymer-grafted multiwall carbon nanotubes functionalized by nitrene chemistry: effect on cooperativity and phase miscibility.

The demixing of polystyrene (PS) and poly(vinyl methylether) (PVME) was systematically investigated in the presence of surface functionalized multiwall carbon nanotubes (MWNTs) by melt rheology. As PS-PVME blends are weakly interacting blends, the contribution of conformational entropy increases, resulting in thermo-rheological complexity wherein the concentration fluctuation persists even beyond the critical demixing temperature. These phenomenal changes were followed here in the presence of MWNTs with different surface functional groups. Polystyrene was synthesised by atom transfer radical polymerization and was immobilized onto carboxyl acid functionalized multiwall carbon nanotubes (COOH-MWNTs) via nitrene chemistry in order to improve the phase miscibility in PS-PVME blends. Interestingly, blends with 0.25 wt% polystyrene grafted multiwall carbon nanotubes (PS-g-MWNTs) delayed the spinodal decomposition temperature in the blends by ∼33 °C with respect to both control blends and those with COOH-MWNTs. While the localization of COOH-MWNTs in PVME was explained from a thermodynamic point of view, the localization of PS-g-MWNTs was understood to result from favorable PS-PVME contact and the degree of surface coverage of PS on the surface of MWNTs. The length of the cooperative rearranging region (ξ) decreased in presence of PS-g-MWNTs, suggesting confinement effects on large scale motions and enhanced interchain concentration fluctuation.

Adsorption of a periodic heteropolymer onto a periodic heterogeneous surface: a directed walk model

The adsorption of a periodic heteropolymer onto a periodic heterogeneous surface is studied using the two-dimensional partially directed walk model of the polymer. We show how the generating function approach developed by Polotsky (2012 J. Phys A: Math. Theor. 45 425004) for the adsorption of a random copolymer onto a random surface can be extended to the case of an arbitrary periodic heteropolymer and a chemically heterogeneous surface: the main equation remains unchanged and the transition probability matrices acquire the special form of circulant matrices of a dimension equal to the corresponding sequence and surface periods, while the particular structure of periods in the polymer and on the surface is encoded in the diagonal ‘interaction matrix’. The developed approach is applied to study the adsorption of a symmetric multiblock copolymer onto a symmetric multiblock two-letter surface. Analysis of the adsorption transition point dependence on polymer and surface block sizes and different sets of polymer–surface interaction parameters reveals interesting ‘odd–even’ and ‘recognition’ effects. Beyond the transition point, temperature dependences of the main conformational and thermodynamic characteristics demonstrate that adsorption can occur as a two-stage process, where binding of the polymer chain to the surface is followed by ‘tuning’ the chain conformations in order to maximize the number of energetically favourable contacts. The two-stage adsorption is characterized by the appearance of the maximum on the heat capacity curves.

Development of a Novel Polishing Pad with a Phyllotactic Pattern, and Experimental Studies

In this paper we discuss the development of a novel polishing pad, and polishing experiments on wafers. The phyllotaxis theory of biology was used to position tin alloy blocks which contained fine diamond abrasive grains on the pad surface. The effects of phyllotactic pattern properties were simulated, and are discussed in detail. Prototype pads were fabricated by use of screen-printing technology. The polishing performance of the pad was tested on wafers. Significant improvements were achieved for polished wafer surface roughness, and its nonconformity was reduced from 3 μm to 1 μm. The suggested range of the diameter of the tin alloy block and the phyllotactic coefficient were from 1.9 mm to 2.1 mm and from 2.0 to 2.2, respectively. These improvements can be attributed to the phyllotactic distribution of the tin alloy blocks, which resulted in favorable contact pressure and temperature distributions, slurry flow, and removal of waste between the polishing pad and the workpiece.

Solution Structure of Calmodulin Bound to the Binding Domain of the HIV-1 Matrix Protein

Subcellular distribution of calmodulin (CaM) in human immunodeficiency virus type-1 (HIV-1)-infected cells is distinct from that observed in uninfected cells. CaM co-localizes and interacts with the HIV-1 Gag protein in the cytosol of infected cells. Although it has been shown that binding of Gag to CaM is mediated by the matrix (MA) domain, the structural details of this interaction are not known. We have recently shown that binding of CaM to MA induces a conformational change that triggers myristate exposure, and that the CaM-binding domain of MA is confined to a region spanning residues 8-43 (MA-(8-43)). Here, we present the NMR structure of CaM bound to MA-(8-43). Our data revealed that MA-(8-43), which contains a novel CaM-binding motif, binds to CaM in an antiparallel mode with the N-terminal helix (α1) anchored to the CaM C-terminal lobe, and the C-terminal helix (α2) of MA-(8-43) bound to the N-terminal lobe of CaM. The CaM protein preserves a semiextended conformation. Binding of MA-(8-43) to CaM is mediated by numerous hydrophobic interactions and stabilized by favorable electrostatic contacts. Our structural data are consistent with the findings that CaM induces unfolding of the MA protein to have access to helices α1 and α2. It is noteworthy that several MA residues involved in CaM binding have been previously implicated in membrane binding, envelope incorporation, and particle production. The present findings may ultimately help in identification of the functional role of CaM in HIV-1 replication.

Trusting Communities and Bigger In‐Groups: Social Capital, Interracial Contact Climate, and Common In‐Group Categorization

Contact with members of different groups can reduce prejudice and encourage people to recategorize members of other social categories. This research examines individual‐level social capital—one's experience with trust, reciprocity norms, and engagement within a given community—as a construct that predicts contact climate and recategorization. People who have high levels of social capital within a community are more likely to perceive a positive interracial contact climate. High social capital and a favorable contact climate can encourage people to focus on their shared identity as members of that community. Two studies support the claim that social capital predicts intergroup processes. Study 1 tests a cross‐sectional mediation model linking individual‐level social capital to perceptions of the contact climate, common in‐group categorization, and racial out‐group attitudes. Study 2 presents longitudinal data demonstrating that social capital's cross‐lagged effects on contact climate, categorization, and racial out‐group attitudes are stronger than their reverse effects. Implications for diversity research and community applications are discussed.

电磁发射枢轨界面初始接触状态研究

Sliding interface status during whole electromagnetic rail launch process depends on contact status after initial assembly in which initial contact force between armature and rails(A-R) is provided by trailing arm elastic deformation in the C-armature rail launcher, which influences launcher system efficiency and rail lifespan. This paper focuses on the contact status of initial C-armature assembly of rail launcher with constructing the contact model for simulating computation and designing many groups of experiments for contrast testing. Considering safe deformable limits of armature material, variation laws of contact pressure, contact region(area) and contact force are analyzed under conditions of small-range feasible heads and tail sizes. Interferential proportion is proposed as a contact status dependent key parameter. Contact region transformed from tail to head of trailing arm as interferential proportion increasing, maximum of contact area is about half of whole outer surface of trailing arm. Optimal contact status for favorable electric contact and engineering implement technique are also discussed.

Effects of Energetic Heterogeneity on Protein Folding Dynamics Across Many Non-Homologous Proteins

Native structure based models (SBMs, “Go-models”) are based on energy landscape theory and the principle of minimal frustration [1,2]. Using this framework strongly reduces computational demands and allows us to investigate the influence of the contact-energy weight onto the folding process for many different protein families. A large set (approx. 200) of non-homologous monomeric proteins sized from 50-150 amino acids are simulated on a coarse-grained level, representing each amino acid by a single bead. A fully automatized workflow implemented with the help of eSBMTools [3] allows to quantify typical folding properties like phi-values, folding free energy landscapes and transition state ensembles (TSEs) for the simulated proteins.Conventional SBMs use sequence independent homogeneous energy weights for the native contact energy. We compare these “vanilla” models with sequence dependent heterogeneous “flavored” energy weights as introduced by Miyazawa and Jernigan [4]. Subsequently, the dynamics of forming TSEs are compared by the sequential formation of tertiary interfaces between secondary structure elements in vanilla and flavored simulations. We find that, despite the energetic dissimilarity, the sequential ordering is similar between both types of simulations and appears as a robust property. This suggests that protein folding dynamics are strongly influenced by the native protein topology.1. Onuchic, J.N. and P.G. Wolynes, Theory of protein folding. Curr. Opin. Struct. Bio., 2004. 14(1): p. 70-75.2. Schug, A. and J.N. Onuchic, Current opinion in pharmacology, 2010. 10(6): p. 709-14.3. Lutz, B., C. Sinner, G. Heuermann, A. Verma, and A. Schug, eSBMTools1.0: enhanced native structure-based modeling tools. Bioinformatics, 2013. doi:10.1093/bioinformatics/btt478.4. Miyazawa, S. and R.L. Jernigan, Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. Journal of Molecular Biology, 1996. 256(3): p. 623-44.

3D models of human ERα and ERβ complexed with coumestrol

Coumestrol, a phytoestrogen found in alfalfa, clover, and beans, has nM affinity for both estrogen receptor-α [ERα] and ERβ. Recently, a novel activity of coumestrol was reported: coumestrol binding to human ERβ represses microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, estradiol binding to ERβ had little or no effect on repression of microglia-mediated inflammation. Coumestrol and estradiol have several structural differences, which suggest that each ligand could induce different conformations in ERβ and, thus, different transcriptional responses in brain microglia. To begin to understand how coumestrol binds to ERβ and ERα, we constructed 3D models of coumestrol with human ERβ and ERα, which were compared to the structures of these ERs with estradiol. Of four possible orientations of coumestrol in ERα and ERβ, one orientation had the most favorable contacts with both ERs. Other phytochemicals may activate ERβ and inhibit inflammation in brain microglia and be useful therapeutics for inflammatory conditions in the brain.

Structural stability of diffusion barriers in thermoelectric SbTe: From first-principles calculations to experimental results

This study involved developing robust diffusion barrier for n-type antimony telluride (SbTe) thermoelectric devices. Compared to conventional Ni barrier, the mid-band metals of Ta and TaN with favored ohmic-like contact exhibited smaller diffusion tail because of structurally stable interface on SbTe, which have been supported by first-principles calculations and demonstrated by experimental results. Furthermore, the TaN barrier has strong ionic Ta–N bonding and a high total energy of −4.7eV/atom that could effectively suppress the formation of SbTe-compounds interfacial layer.

“Ask me what I read”: readers' advisory and immigrant adaptation

Purpose – The purpose of this paper is to investigate the potential of readers' advisory (RA) in libraries to help immigrants with psychological and socio-cultural adaptation in a new country. Design/methodology/approach – The data were empirically collected from a sample of Russian-speaking immigrant readers residing in the Greater Toronto Area, Ontario, Canada, by means of background surveys and in-depth interviews. Findings – The RA interaction is not merely a conversation about leisure books; it is a powerful intercultural encounter that has the potential to raise the levels of intimacy and attraction between host and immigrant populations, break negative stereotypes, help to build shared networks and create favorable contacts, change intergroup attitudes, and improve readers' mastery of the second language and knowledge of a new country. Originality/value – This article makes a contribution to three areas related to RA. It provides insight into the views and perceptions of RA by a selected group of readers; it gives voice to immigrant readers whose experiences with RA are particularly under-represented in the Library and Information Science literature; and it conceptualizes the RA interaction as an intercultural encounter, using the uncertainty reduction based theory of intercultural adaptation to frame the discussion.

Encapsulation of a Rhodamine Dye within a Bile Acid Binding Protein: Toward Water Processable Functional Bio Host–Guest Materials

New strategies are requested for the preparation of bioinspired host-guest complexes to be employed in technologically relevant applications, as sensors and optoelectronic devices. We report here a new approach employing a single monomeric protein as host for the strongly fluorescent rhodamine dye. The selected protein, belonging to the intracellular lipid binding protein family, fully encapsulates one rhodamine molecule inside its cavity forming a host-guest complex stabilized by H and π-hydrogen bonds, a salt bridge, and favorable hydrophobic contacts, as revealed by the NMR derived structural model. The protein-dye solutions are easily processable and form homogeneous thin films exhibiting excellent photophysical and morphological properties, as derived from photoluminescence and AFM data. The obtained results represent the proof of concept of the viability of this bio host-guest system for the development of bioinspired optoelectronic devices.

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined “fuzziness”, often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs.