Effects on semiflexible polymer dynamics

The influence of hydrodynamic screening near a surface on the dynamics of a single semiflexible polymer is studied by means of Brownian dynamics simulations and hydrodynamicmean field theory. The polymer motion is characterized in terms of the mean squared displacements of the end-monomers, the end-to-end vector, and the scalar end-to-end distance. In order to control hydrodynamic screening effects, the polymer is confined to a plane at a fixed separation from the wall. When gradually decreasing this separation, a crossover from Zimm-type towards Rouse (free-draining) polymerdynamics is induced. However, this crossover is rather slow and the free-draining limit is not completely reached—substantial deviations from Rouse-like dynamics are registered in both simulations and theory—even at distances of the polymer from the wall on the order of the monomer size. Remarkably, the effect of surface-induced screening of hydrodynamic interactions sensitively depends on the type of dynamic observable considered. For vectorial quantities such as the end-to-end vector, hydrodynamic interactions are important and therefore surface screening effects are sizeable. For a scalar quantity such as the end- to-end distance, on the other hand, hydrodynamic interactions are less important, but a pronounced dependence of dynamic scaling exponents on the persistence length to contour length ratio becomes noticeable. Our findings are discussed against the background of single-molecule experiments on f-actin [L. Le Goff et al., Phys. Rev. Lett.89, 258101 (2002)]10.1103/PhysRevLett.89.258101

Anomalous Anisotropic Diffusion Dynamics of Hydration Water at Lipid Membranes

The diffusional water dynamics in the hydration layer of a dipalmitoylphosphatidylcholine bilayer is studied using molecular dynamics simulations. By mapping the perpendicular water motion on the ordinary diffusion equation, we disentangle free energetic and friction effects and show that perpendicular diffusion is strongly reduced. The lateral water motion exhibits anomalous diffusion up to several nanoseconds and is characterized by even further decreased diffusion coefficients, which by comparison with coarse grained simulations are explained by the transient corrugated effective free energy landscape imposed by the lipids. This is in contrast to homogenous surfaces, where boundary hydrodynamic theory quantitatively predicts the anisotropy of water diffusion

DNA-Protein Binding Rates: Bending Fluctuation and Hydrodynamic Coupling Effects

We investigate diffusion-limited reactions between a diffusing particle and a target site on a semiflexible polymer, a key factor determining the kinetics of DNA-protein binding and polymerization of cytoskeletal filaments. Our theory focuses on two competing effects: polymer shape fluctuations, which speed up association, and the hydrodynamic coupling between the diffusing particle and the chain, which slows down association. Polymer bending fluctuations are described using a mean field dynamical theory, while the hydrodynamic coupling between polymer and particle is incorporated through a simple heuristic approximation. Both of these we validate through comparison with Brownian dynamics simulations. Neither of the effects has been fully considered before in the biophysical context, and we show they are necessary to form accurate estimates of reaction processes. The association rate depends on the stiffness of the polymer and the particle size, exhibiting a maximum for intermediate persistence length and a minimum for intermediate particle radius. In the parameter range relevant to DNA-protein binding, the rate increase is up to 100% compared to the Smoluchowski result for simple center-of-mass motion. The quantitative predictions made by the theory can be tested experimentally.Comment: 21 pages, 11 figures, 1 tabl

Auto- and cross-power spectral analysis of dual trap optical tweezer experiments using Bayesian inference

The thermal fluctuations of micron-sized beads in dual trap optical tweezer experiments contain complete dynamic information about the viscoelastic properties of the embedding medium and—if present—macromolecular constructs connecting the two beads. To quantitatively interpret the spectral properties of the measured signals, a detailed understanding of the instrumental characteristics is required. To this end, we present a theoretical description of the signal processing in a typical dual trap optical tweezer experiment accounting for polarization crosstalk and instrumental noise and discuss the effect of finite statistics. To infer the unknown parameters from experimental data, a maximum likelihood method based on the statistical properties of the stochastic signals is derived. In a first step, the method can be used for calibration purposes: We propose a scheme involving three consecutive measurements (both traps empty, first one occupied and second empty, and vice versa), by which all instrumental and physical parameters of the setup are determined. We test our approach for a simple model system, namely a pair of unconnected, but hydrodynamically interacting spheres. The comparison to theoretical predictions based on instantaneous as well as retarded hydrodynamics emphasizes the importance of hydrodynamic retardation effects due to vorticity diffusion in the fluid. For more complex experimental scenarios, where macromolecular constructs are tethered between the two beads, the same maximum likelihood method in conjunction with dynamic deconvolution theory will in a second step allow one to determine the viscoelastic properties of the tethered element connecting the two beads

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

The mammalian gene function resource: The International Knockout Mouse Consortium

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat