Optimizing the design of oligonucleotides for homology directed gene targeting.

BACKGROUND: Gene targeting depends on the ability of cells to use homologous recombination to integrate exogenous DNA into their own genome. A robust mechanistic model of homologous recombination is necessary to fully exploit gene targeting for therapeutic benefit. METHODOLOGY/PRINCIPAL FINDINGS: In this work, our recently developed numerical simulation model for homology search is employed to develop rules for the design of oligonucleotides used in gene targeting. A Metropolis Monte-Carlo algorithm is used to predict the pairing dynamics of an oligonucleotide with the target double-stranded DNA. The model calculates the base-alignment between a long, target double-stranded DNA and a probe nucleoprotein filament comprised of homologous recombination proteins (Rad51 or RecA) polymerized on a single strand DNA. In this study, we considered different sizes of oligonucleotides containing 1 or 3 base heterologies with the target; different positions on the probe were tested to investigate the effect of the mismatch position on the pairing dynamics and stability. We show that the optimal design is a compromise between the mean time to reach a perfect alignment between the two molecules and the stability of the complex. CONCLUSION AND SIGNIFICANCE: A single heterology can be placed anywhere without significantly affecting the stability of the triplex. In the case of three consecutive heterologies, our modeling recommends using long oligonucleotides (at least 35 bases) in which the heterologous sequences are positioned at an intermediate position. Oligonucleotides should not contain more than 10% consecutive heterologies to guarantee a stable pairing with the target dsDNA. Theoretical modeling cannot replace experiments, but we believe that our model can considerably accelerate optimization of oligonucleotides for gene therapy by predicting their pairing dynamics with the target dsDNA.

Many-body localization study in low-density electron gases: do metals exist in two dimensions?

Using a combination of ground state quantum Monte Carlo and finite size scaling techniques, we perform a systematic study of the effect of Coulomb interaction on the localization length of a disordered two-dimensional electron gas. We find that correlations delocalize the 2D system. In the absence of valley degeneracy (as in GaAs heterostructures), this delocalization effect corresponds to a finite increase of the localization length. The delocalization is much more dramatic in the presence of valley degeneracy [as in Si metal-oxide-semiconductor field-effect transistors], where the localization length increases drastically. We find that a simple mechanism accounts for the main features of the metallic behavior observed in two-dimensional gases. Our findings support the claim that this behavior is a genuine effect of the presence of interactions, yet that the system is not a "true" metal in the thermodynamic sense.

Persistent currents in one dimension: the counterpart of Leggett's theorem.

We discuss the sign of the persistent current of N electrons in one dimensional rings. Using a topology argument, we establish lower bounds for the free energy in the presence of arbitrary electron-electron interactions and external potentials. Those bounds are the counterparts of upper bounds derived by Leggett. Rings with odd (even) numbers of polarized electrons are always diamagnetic (paramagnetic). We show that unpolarized electrons with N being a multiple of four exhibit either paramagnetic behavior or a superconductorlike current-phase relation.

Numerical finite size scaling approach to many-body localization.

We develop a numerical technique to study Anderson localization in interacting electronic systems. The ground state of the disordered system is calculated with quantum Monte Carlo simulations while the localization properties are extracted from the "Thouless conductance" g, i.e., the curvature of the energy with respect to an Aharonov-Bohm flux. We apply our method to polarized electrons in a two-dimensional system of size L. We recover the well-known universal beta(g)=dlogg/dlogL one parameter scaling function without interaction. Upon switching on the interaction, we find that beta(g) is unchanged while the system flows toward the insulating limit. We conclude that polarized electrons in two dimensions stay in an insulating state in the presence of weak to moderate electron-electron correlations.