Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene.

Short structural variants-variants other than single nucleotide polymorphisms-are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation have not been discovered. Here, we study simple sequence repeats (SSRs), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding. In this study, we focus on the SSR termed Rep1, which was associated with Parkinson's disease (PD) and has been implicated in the cis-regulation of the PD-risk SNCA gene. We show that Rep1 acts via the non-consensus binding mechanism to affect the binding of transcription factors from the GATA and ELK families to their specific sites located right next to the Rep1 repeat. Next, we performed an expression analysis to further our understanding regarding the GATA and ELK family members that are potentially relevant for SNCA transcriptional regulation in health and disease. Our analysis indicates a potential role for GATA2, consistent with previous reports. Our study proposes non-consensus transcription factor binding as a potential mechanism through which noncoding repeat variants could exert their pathogenic effects by regulating gene expression.

Statistically enhanced promiscuity of structurally correlated patterns.

We predict that patterns with correlated surface density of atoms have statistically higher promiscuity (ability to bind stronger to an arbitrary pattern) as compared with noncorrelated patterns with the same average surface density. We suggest that this constitutes a generic design principle for highly connected proteins (hubs) in protein interaction networks. We develop an analytical theory for this effect. We show that our key predictions are generic and independent, qualitatively, on the specific form of the interatomic interaction potential, provided it has a finite range.

Structural similarity enhances interaction propensity of proteins.

We study statistical properties of interacting protein-like surfaces and predict two strong, related effects: (i) statistically enhanced self-attraction of proteins; (ii) statistically enhanced attraction of proteins with similar structures. The effects originate in the fact that the probability to find a pattern self-match between two identical, even randomly organized interacting protein surfaces is always higher compared with the probability for a pattern match between two different, promiscuous protein surfaces. This theoretical finding explains statistical prevalence of homodimers in protein-protein interaction networks reported earlier. Further, our findings are confirmed by the analysis of curated database of protein complexes that showed highly statistically significant overrepresentation of dimers formed by structurally similar proteins with highly divergent sequences ("superfamily heterodimers"). We suggest that promiscuous homodimeric interactions pose strong competitive interactions for heterodimers evolved from homodimers. Such evolutionary bottleneck is overcome using the negative design evolutionary pressure applied against promiscuous homodimer formation. This is achieved through the formation of highly specific contacts formed by charged residues as demonstrated both in model and real superfamily heterodimers.

Statistically enhanced self-attraction of random patterns.

In this work we develop a theory of interaction of randomly patterned surfaces as a generic prototype model of protein-protein interactions. The theory predicts that pairs of randomly superimposed identical (homodimeric) random patterns have always twice as large magnitude of the energy fluctuations with respect to their mutual orientation, as compared with pairs of different (heterodimeric) random patterns. The amplitude of the energy fluctuations is proportional to the square of the average pattern density, to the square of the amplitude of the potential and its characteristic length, and scales linearly with the area of surfaces. The greater dispersion of interaction energies in the ensemble of homodimers implies that strongly attractive complexes of random surfaces are much more likely to be homodimers, rather than heterodimers. Our findings suggest a plausible physical reason for the anomalously high fraction of homodimers observed in real protein interaction networks.

Surface and bulk dissolution properties, and selectivity of DNA-linked nanoparticle assemblies.

Using a simple mean-field model, we analyze the surface and bulk dissolution properties of DNA-linked nanoparticle assemblies. We find that the dissolution temperature and the sharpness of the dissolution profiles increase with the grafting density of the single-stranded DNA "probes" on the surface of colloids. The surface grafting density is controlled by the linker occupation number, in analogy with quantum particles obeying fractional statistics. The dissolution temperature increases logarithmically with the salt concentration. This is in agreement with the experimental findings [R. Jin, G. Wu, Z. Li, C. A. Mirkin, and G. C. Schatz, J. Am. Chem. Soc. 125, 1643 (2003)]. By exploiting the unique phase behavior of DNA-coated colloids, it should be possible to detect multiple "targets" in a single experiment by essentially mapping the DNA base-pair sequence onto the phase behavior of DNA-linked nanoparticle solution.

Multiple stalk formation as a pathway of defect-induced membrane fusion.

We propose that the first stage of membrane fusion need not be the formation of a single stalk. Instead, we consider a scenario for defect-induced membrane fusion that proceeds cooperatively via multiple stalk formation. The defects (stalks or pores) attract each other via membrane-mediated capillary interactions that result in a condensation transition of the defects. The resulting dense phase of stalks corresponds to the so-called fusion intermediate.

Phase behavior and selectivity of DNA-linked nanoparticle assemblies.

We propose a model that can account for the experimentally observed phase behavior of DNA-nanoparticle assemblies [J. Am. Chem. Soc. 125, 1643 (2003)]; Science 289, 1757 (2000)]]. The binding of DNA-coated nanoparticles by dissolved DNA linkers can be described by exploiting an analogy with quantum particles obeying fractional statistics. In accordance with experimental findings, we predict that the phase-separation temperature of the nanocolloids increases with the DNA coverage of the colloidal surface. Upon the addition of salt, the demixing temperature increases logarithmically with the salt concentration. Our analysis suggests an experimental strategy to map microscopic DNA sequences onto the macroscopic phase behavior of the DNA-nanoparticle solutions. Such an approach should enhance the efficiency of methods to detect (single) mutations in specific DNA sequences.

Slow fluctuations in enhanced Raman scattering and surface roughness relaxation.

We propose an explanation for the recently measured slow fluctuations and "blinking" in the surface-enhanced Raman scattering spectrum of single molecules adsorbed on a silver colloidal particle. We suggest that these fluctuations may be related to the dynamic relaxation of the surface roughness on the nanometer scale and show that there are two classes of roughness with qualitatively different dynamics. The predictions agree with the measurements of surface roughness relaxation. Using a theoretical model for the kinetics of surface roughness relaxation in the presence of charges and optical electrical fields, we predict that the high-frequency electromagnetic field increases both the effective surface tension and the surface diffusion constant and thus accelerates the surface smoothing kinetics and time scale of the Raman fluctuations in a manner that is linear with the laser power intensity, while the addition of salt retards the surface relaxation kinetics and increases the time scale of the fluctuations. These predictions are in qualitative agreement with the Raman experiments.

Charge fluctuations and counterion condensation.

We predict a condensation phenomenon in an overall neutral system, consisting of a single charged plate and its oppositely charged counterions. Based on the "two-fluid" model, in which the counterions are divided into a "free" and a "condensed" fraction, we argue that for high surface charge, fluctuations can lead to a phase transition in which a large fraction of counterions is condensed. Furthermore, we show that depending on the valence, the condensation is either a first-order or a smooth transition.

Fluctuations and ordering in macroion suspensions.

We calculate the static properties of macroion density fluctuations in both bulk and in confined, strongly interacting, macroion suspensions (macroions interact via the Derjaguin-Landau-Verwey-Overbeek potential) in terms of a simple density-functional ansatz. We show how to map a strongly interacting suspension to a weakly interacting one and obtain the renormalized charge, diameter and scattering structure factors analytically. The model is extrapolated to predict crystalline order in terms of a Hansen-Verlet-type of criterion as well as an effective hard-sphere crystallization condition, and good agreement with simulations is found. The increase in correlations observed in recent experiments in two, confined layers is demonstrated.

Pressure of correlated layer-charge and counterion fluctuations in charged thin films.

We predict the fluctuation contribution to the interaction between two surfaces with both mobile layer charges and delocalized counterions. The correlation (coupling) between the layer-charge fluctuations and the counterion fluctuations (around a piecewise homogeneous mean-field density profile) is taken into account in the Gaussian approximation. We find that this correlation significantly increases the magnitude of the interlayer fluctuation attraction. The counterion fluctuation pressure is calculated as a function of the intersurface distance and we show how the large and small distance limits correspond to three-dimensional (3D) and 2D fluctuations, respectively. In addition, we predict the charge density-density correlation functions. Experimental implications of the model are discussed.