@article{PulkkinenMetzler2015,
  author    = {Pulkkinen, Otto and Metzler, Ralf},
  title     = {Variance-corrected Michaelis-Menten equation predicts transient rates of single-enzyme reactions and response times in bacterial gene-regulation},
  series = {Scientific reports},
  volume    = {5},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/srep17820},
  pages     = {11},
  year      = {2015},
  abstract  = {Many chemical reactions in biological cells occur at very low concentrations of constituent molecules. Thus, transcriptional gene-regulation is often controlled by poorly expressed transcription-factors, such as E. coli lac repressor with few tens of copies. Here we study the effects of inherent concentration fluctuations of substrate-molecules on the seminal Michaelis-Menten scheme of biochemical reactions. We present a universal correction to the Michaelis-Menten equation for the reaction-rates. The relevance and validity of this correction for enzymatic reactions and intracellular gene-regulation is demonstrated. Our analytical theory and simulation results confirm that the proposed variance-corrected Michaelis-Menten equation predicts the rate of reactions with remarkable accuracy even in the presence of large non-equilibrium concentration fluctuations. The major advantage of our approach is that it involves only the mean and variance of the substrate-molecule concentration. Our theory is therefore accessible to experiments and not specific to the exact source of the concentration fluctuations.},
  language  = {en}
}
@misc{PulkkinenMetzler2015,
  author    = {Pulkkinen, Otto and Metzler, Ralf},
  title     = {Variance-corrected Michaelis-Menten equation predicts transient rates of single-enzyme reactions and response times in bacterial gene-regulation},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-86632},
  year      = {2015},
  abstract  = {Many chemical reactions in biological cells occur at very low concentrations of constituent molecules. Thus, transcriptional gene-regulation is often controlled by poorly expressed transcription-factors, such as E.coli lac repressor with few tens of copies. Here we study the effects of inherent concentration fluctuations of substrate-molecules on the seminal Michaelis-Menten scheme of biochemical reactions. We present a universal correction to the Michaelis-Menten equation for the reaction-rates. The relevance and validity of this correction for enzymatic reactions and intracellular gene-regulation is demonstrated. Our analytical theory and simulation results confirm that the proposed variance-corrected Michaelis-Menten equation predicts the rate of reactions with remarkable accuracy even in the presence of large non-equilibrium concentration fluctuations. The major advantage of our approach is that it involves only the mean and variance of the substrate-molecule concentration. Our theory is therefore accessible to experiments and not specific to the exact source of the concentration fluctuations.},
  language  = {en}
}
@article{PulkkinenMetzler2015,
  author    = {Pulkkinen, Otto and Metzler, Ralf},
  title     = {Variance-corrected Michaelis-Menten equation predicts transient rates of single-enzyme reactions and response times in bacterial gene-regulation},
  series = {Scientific reports},
  journal   = {Scientific reports},
  number    = {5},
  publisher = {Nature Publishing Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/srep17820},
  year      = {2015},
  abstract  = {Many chemical reactions in biological cells occur at very low concentrations of constituent molecules. Thus, transcriptional gene-regulation is often controlled by poorly expressed transcription-factors, such as E.coli lac repressor with few tens of copies. Here we study the effects of inherent concentration fluctuations of substrate-molecules on the seminal Michaelis-Menten scheme of biochemical reactions. We present a universal correction to the Michaelis-Menten equation for the reaction-rates. The relevance and validity of this correction for enzymatic reactions and intracellular gene-regulation is demonstrated. Our analytical theory and simulation results confirm that the proposed variance-corrected Michaelis-Menten equation predicts the rate of reactions with remarkable accuracy even in the presence of large non-equilibrium concentration fluctuations. The major advantage of our approach is that it involves only the mean and variance of the substrate-molecule concentration. Our theory is therefore accessible to experiments and not specific to the exact source of the concentration fluctuations.},
  language  = {en}
}
@article{BodrovaChechkinCherstvyetal.2015,
  author    = {Bodrova, Anna S. and Chechkin, Aleksei V. and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Ultraslow scaled Brownian motion},
  series = {New journal of physics : the open-access journal for physics},
  volume    = {17},
  journal   = {New journal of physics : the open-access journal for physics},
  publisher = {IOP Publ. Ltd.},
  address   = {Bristol},
  issn      = {1367-2630},
  doi       = {10.1088/1367-2630/17/6/063038},
  pages     = {16},
  year      = {2015},
  abstract  = {We define and study in detail utraslow scaled Brownian motion (USBM) characterized by a time dependent diffusion coefficient of the form D(t) similar or equal to 1/t. For unconfined motion the mean squared displacement (MSD) of USBM exhibits an ultraslow, logarithmic growth as function of time, in contrast to the conventional scaled Brownian motion. In a harmonic potential the MSD of USBM does not saturate but asymptotically decays inverse-proportionally to time, reflecting the highly non-stationary character of the process. We show that the process is weakly non-ergodic in the sense that the time averaged MSD does not converge to the regular MSD even at long times, and for unconfined motion combines a linear lag time dependence with a logarithmic term. The weakly non-ergodic behaviour is quantified in terms of the ergodicity breaking parameter. The USBM process is also shown to be ageing: observables of the system depend on the time gap between initiation of the test particle and start of the measurement of its motion. Our analytical results are shown to agree excellently with extensive computer simulations.},
  language  = {en}
}
@article{MetzlerCherstvyChechkinetal.2015,
  author    = {Metzler, Ralf and Cherstvy, Andrey G. and Chechkin, Aleksei V. and Bodrova, Anna S.},
  title     = {Ultraslow scaled Brownian motion},
  series = {New journal of physics : the open-access journal for physics},
  volume    = {17},
  journal   = {New journal of physics : the open-access journal for physics},
  number    = {063038},
  publisher = {Dt. Physikalische Ges., IOP},
  address   = {Bad Honnef, London},
  issn      = {1367-2630},
  doi       = {10.1088/1367-2630/17/6/063038},
  year      = {2015},
  abstract  = {We define and study in detail utraslow scaled Brownian motion (USBM) characterized by a time dependent diffusion coefficient of the form . For unconfined motion the mean squared displacement (MSD) of USBM exhibits an ultraslow, logarithmic growth as function of time, in contrast to the conventional scaled Brownian motion. In a harmonic potential the MSD of USBM does not saturate but asymptotically decays inverse-proportionally to time, reflecting the highly non-stationary character of the process. We show that the process is weakly non-ergodic in the sense that the time averaged MSD does not converge to the regular MSD even at long times, and for unconfined motion combines a linear lag time dependence with a logarithmic term. The weakly non-ergodic behaviour is quantified in terms of the ergodicity breaking parameter. The USBM process is also shown to be ageing: observables of the system depend on the time gap between initiation of the test particle and start of the measurement of its motion. Our analytical results are shown to agree excellently with extensive computer simulations.},
  language  = {en}
}
@misc{MetzlerCherstvyChechkinetal.2015,
  author    = {Metzler, Ralf and Cherstvy, Andrey G. and Chechkin, Aleksei V. and Bodrova, Anna S.},
  title     = {Ultraslow scaled Brownian motion},
  series = {New journal of physics : the open-access journal for physics},
  journal   = {New journal of physics : the open-access journal for physics},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-78618},
  year      = {2015},
  abstract  = {We define and study in detail utraslow scaled Brownian motion (USBM) characterized by a time dependent diffusion coefficient of the form . For unconfined motion the mean squared displacement (MSD) of USBM exhibits an ultraslow, logarithmic growth as function of time, in contrast to the conventional scaled Brownian motion. In a harmonic potential the MSD of USBM does not saturate but asymptotically decays inverse-proportionally to time, reflecting the highly non-stationary character of the process. We show that the process is weakly non-ergodic in the sense that the time averaged MSD does not converge to the regular MSD even at long times, and for unconfined motion combines a linear lag time dependence with a logarithmic term. The weakly non-ergodic behaviour is quantified in terms of the ergodicity breaking parameter. The USBM process is also shown to be ageing: observables of the system depend on the time gap between initiation of the test particle and start of the measurement of its motion. Our analytical results are shown to agree excellently with extensive computer simulations.},
  language  = {en}
}
@article{RevereyJeonBaoetal.2015,
  author    = {Reverey, Julia F. and Jeon, Jae-Hyung and Bao, Han and Leippe, Matthias and Metzler, Ralf and Selhuber-Unkel, Christine},
  title     = {Superdiffusion dominates intracellular particle motion in the supercrowded cytoplasm of pathogenic Acanthamoeba castellanii},
  series = {Scientific reports},
  volume    = {5},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/srep11690},
  pages     = {14},
  year      = {2015},
  abstract  = {Acanthamoebae are free-living protists and human pathogens, whose cellular functions and pathogenicity strongly depend on the transport of intracellular vesicles and granules through the cytosol. Using high-speed live cell imaging in combination with single-particle tracking analysis, we show here that the motion of endogenous intracellular particles in the size range from a few hundred nanometers to several micrometers in Acanthamoeba castellanii is strongly superdiffusive and influenced by cell locomotion, cytoskeletal elements, and myosin II. We demonstrate that cell locomotion significantly contributes to intracellular particle motion, but is clearly not the only origin of superdiffusivity. By analyzing the contribution of microtubules, actin, and myosin II motors we show that myosin II is a major driving force of intracellular motion in A. castellanii. The cytoplasm of A. castellanii is supercrowded with intracellular vesicles and granules, such that significant intracellular motion can only be achieved by actively driven motion, while purely thermally driven diffusion is negligible.},
  language  = {en}
}
@article{ShinCherstvyMetzler2015,
  author    = {Shin, Jaeoh and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Self-subdiffusion in solutions of star-shaped crowders: non-monotonic effects of inter-particle interactions},
  series = {New journal of physics : the open-access journal for physics},
  volume    = {17},
  journal   = {New journal of physics : the open-access journal for physics},
  publisher = {IOP Publ. Ltd.},
  address   = {Bristol},
  issn      = {1367-2630},
  doi       = {10.1088/1367-2630/17/11/113028},
  pages     = {12},
  year      = {2015},
  abstract  = {We examine by extensive computer simulations the self-diffusion of anisotropic star-like particles in crowded two-dimensional solutions. We investigate the implications of the area coverage fraction phi of the crowders and the crowder-crowder adhesion properties on the regime of transient anomalous diffusion. We systematically compute the mean squared displacement (MSD) of the particles, their time averaged MSD, and the effective diffusion coefficient. The diffusion is ergodic in the limit of long traces, such that the mean time averaged MSD converges towards the ensemble averaged MSD, and features a small residual amplitude spread of the time averaged MSD from individual trajectories. At intermediate time scales, we quantify the anomalous diffusion in the system. Also, we show that the translational-but not rotational-diffusivity of the particles Dis a nonmonotonic function of the attraction strength between them. Both diffusion coefficients decrease as the power law D(phi) similar to (1 - phi/phi*)(2 ... 2.4) with the area fraction phi occupied by the crowders and the critical value phi*. Our results might be applicable to rationalising the experimental observations of non-Brownian diffusion for a number of standard macromolecular crowders used in vitro to mimic the cytoplasmic conditions of living cells.},
  language  = {en}
}
@article{MetzlerBauerRasmussenetal.2015,
  author    = {Metzler, Ralf and Bauer, Maximilian and Rasmussen, Emil S. and Lomholt, Michael A.},
  title     = {Real sequence effects on the search dynamics of transcription factors on DNA},
  series = {Scientific Reports},
  volume    = {5},
  journal   = {Scientific Reports},
  number    = {10072},
  publisher = {Nature Publishing Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/srep10072},
  year      = {2015},
  abstract  = {Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection. For the probability to detect the target before dissociating from DNA the TF-search times self-consistently depend heavily on whether or not an auxiliary operator (an accessible sequence similar to the main operator) is present in the genome section. Importantly, within our model the extent to which the interconversion rates between search and recognition states depend on the underlying nucleotide sequence is varied. A moderate dependence maximises the capability to distinguish between the main operator and similar sequences. Moreover, these auxiliary operators serve as starting points for DNA looping with the main operator, yielding a spectrum of target detection times spanning several orders of magnitude. Auxiliary operators are shown to act as funnels facilitating target detection by TFs.},
  language  = {en}
}
@misc{MetzlerBauerRasmussenetal.2015,
  author    = {Metzler, Ralf and Bauer, Maximilian and Rasmussen, Emil S. and Lomholt, Michael A.},
  title     = {Real sequence effects on the search dynamics of transcription factors on DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-79411},
  year      = {2015},
  abstract  = {Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection. For the probability to detect the target before dissociating from DNA the TF-search times self-consistently depend heavily on whether or not an auxiliary operator (an accessible sequence similar to the main operator) is present in the genome section. Importantly, within our model the extent to which the interconversion rates between search and recognition states depend on the underlying nucleotide sequence is varied. A moderate dependence maximises the capability to distinguish between the main operator and similar sequences. Moreover, these auxiliary operators serve as starting points for DNA looping with the main operator, yielding a spectrum of target detection times spanning several orders of magnitude. Auxiliary operators are shown to act as funnels facilitating target detection by TFs.},
  language  = {en}
}
@article{BauerRasmussenLomholtetal.2015,
  author    = {Bauer, Maximilian and Rasmussen, Emil S. and Lomholt, Michael A. and Metzler, Ralf},
  title     = {Real sequence effects on the search dynamics of transcription factors on DNA},
  series = {Scientific reports},
  volume    = {5},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/srep10072},
  pages     = {13},
  year      = {2015},
  abstract  = {Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection. For the probability to detect the target before dissociating from DNA the TF-search times self-consistently depend heavily on whether or not an auxiliary operator (an accessible sequence similar to the main operator) is present in the genome section. Importantly, within our model the extent to which the interconversion rates between search and recognition states depend on the underlying nucleotide sequence is varied. A moderate dependence maximises the capability to distinguish between the main operator and similar sequences. Moreover, these auxiliary operators serve as starting points for DNA looping with the main operator, yielding a spectrum of target detection times spanning several orders of magnitude. Auxiliary operators are shown to act as funnels facilitating target detection by TFs.},
  language  = {en}
}
@article{SafdariCherstvyChechkinetal.2015,
  author    = {Safdari, Hadiseh and Cherstvy, Andrey G. and Chechkin, Aleksei V. and Thiel, Felix and Sokolov, Igor M. and Metzler, Ralf},
  title     = {Quantifying the non-ergodicity of scaled Brownian motion},
  series = {Journal of physics : A, Mathematical and theoretical},
  volume    = {48},
  journal   = {Journal of physics : A, Mathematical and theoretical},
  number    = {37},
  publisher = {IOP Publ. Ltd.},
  address   = {Bristol},
  issn      = {1751-8113},
  doi       = {10.1088/1751-8113/48/37/375002},
  pages     = {18},
  year      = {2015},
  abstract  = {We examine the non-ergodic properties of scaled Brownian motion (SBM), a non-stationary stochastic process with a time dependent diffusivity of the form D(t) similar or equal to t(alpha-1). We compute the ergodicity breaking parameter EB in the entire range of scaling exponents a, both analytically and via extensive computer simulations of the stochastic Langevin equation. We demonstrate that in the limit of long trajectory lengths T and short lag times Delta the EB parameter as function of the scaling exponent a has no divergence at alpha - 1/2 and present the asymptotes for EB in different limits. We generalize the analytical and simulations results for the time averaged and ergodic properties of SBM in the presence of ageing, that is, when the observation of the system starts only a finite time span after its initiation. The approach developed here for the calculation of the higher time averaged moments of the particle displacement can be applied to derive the ergodic properties of other stochastic processes such as fractional Brownian motion.},
  language  = {en}
}
@article{BodrovaChechkinCherstvyetal.2015,
  author    = {Bodrova, Anna and Chechkin, Aleksei V. and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Quantifying non-ergodic dynamics of force-free granular gases},
  series = {Physical chemistry, chemical physics : PCCP ; a journal of European Chemical Societies},
  journal   = {Physical chemistry, chemical physics : PCCP ; a journal of European Chemical Societies},
  number    = {17},
  issn      = {1463-9084},
  doi       = {10.1039/C5CP02824H},
  pages     = {21791 -- 21798},
  year      = {2015},
  abstract  = {Brownianmotion is ergodic in the Boltzmann-Khinchin sense that long time averages of physical observables such as the mean squared displacement provide the same information as the corresponding ensemble average, even at out-of-equilibrium conditions. This property is the fundamental prerequisite for single particle tracking and its analysis in simple liquids. We study analytically and by event-driven molecular dynamics simulations the dynamics of force-free cooling granular gases and reveal a violation of ergodicity in this Boltzmann- Khinchin sense as well as distinct ageing of the system. Such granular gases comprise materials such as dilute gases of stones, sand, various types of powders, or large molecules, and their mixtures are ubiquitous in Nature and technology, in particular in Space. We treat—depending on the physical-chemical properties of the inter-particle interaction upon their pair collisions—both a constant and a velocity-dependent (viscoelastic) restitution coefficient e. Moreover we compare the granular gas dynamics with an effective single particle stochastic model based on an underdamped Langevin equation with time dependent diffusivity. We find that both models share the same behaviour of the ensemble mean squared displacement (MSD) and the velocity correlations in the limit of weak dissipation. Qualitatively, the reported non-ergodic behaviour is generic for granular gases with any realistic dependence of e on the impact velocity of particles.},
  language  = {en}
}
@misc{BodrovaChechkinCherstvyetal.2015,
  author    = {Bodrova, Anna and Chechkin, Aleksei V. and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Quantifying non-ergodic dynamics of force-free granular gases},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-85200},
  year      = {2015},
  abstract  = {Brownianmotion is ergodic in the Boltzmann-Khinchin sense that long time averages of physical observables such as the mean squared displacement provide the same information as the corresponding ensemble average, even at out-of-equilibrium conditions. This property is the fundamental prerequisite for single particle tracking and its analysis in simple liquids. We study analytically and by event-driven molecular dynamics simulations the dynamics of force-free cooling granular gases and reveal a violation of ergodicity in this Boltzmann-Khinchin sense as well as distinct ageing of the system. Such granular gases comprise materials such as dilute gases of stones, sand, various types of powders, or large molecules, and their mixtures are ubiquitous in Nature and technology, in particular in Space. We treat—depending on the physical-chemical properties of the inter-particle interaction upon their pair collisions—both a constant and a velocity-dependent (viscoelastic) restitution coefficient e. Moreover we compare the granular gas dynamics with an effective single particle stochastic model based on an underdamped Langevin equation with time dependent diffusivity. We find that both models share the same behaviour of the ensemble mean squared displacement (MSD) and the velocity correlations in the limit of weak dissipation. Qualitatively, the reported non-ergodic behaviour is generic for granular gases with any realistic dependence of e on the impact velocity of particles.},
  language  = {en}
}
@article{BodrovaChechkinCherstvyetal.2015,
  author    = {Bodrova, Anna and Chechkin, Aleksei V. and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Quantifying non-ergodic dynamics of force-free granular gases},
  series = {Physical chemistry, chemical physics : a journal of European Chemical Societies},
  volume    = {17},
  journal   = {Physical chemistry, chemical physics : a journal of European Chemical Societies},
  number    = {34},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1463-9076},
  doi       = {10.1039/c5cp02824h},
  pages     = {21791 -- 21798},
  year      = {2015},
  abstract  = {Brownian motion is ergodic in the Boltzmann-Khinchin sense that long time averages of physical observables such as the mean squared displacement provide the same information as the corresponding ensemble average, even at out-of-equilibrium conditions. This property is the fundamental prerequisite for single particle tracking and its analysis in simple liquids. We study analytically and by event-driven molecular dynamics simulations the dynamics of force-free cooling granular gases and reveal a violation of ergodicity in this Boltzmann-Khinchin sense as well as distinct ageing of the system. Such granular gases comprise materials such as dilute gases of stones, sand, various types of powders, or large molecules, and their mixtures are ubiquitous in Nature and technology, in particular in Space. We treat-depending on the physical-chemical properties of the inter-particle interaction upon their pair collisions-both a constant and a velocity-dependent (viscoelastic) restitution coefficient epsilon. Moreover we compare the granular gas dynamics with an effective single particle stochastic model based on an underdamped Langevin equation with time dependent diffusivity. We find that both models share the same behaviour of the ensemble mean squared displacement (MSD) and the velocity correlations in the limit of weak dissipation. Qualitatively, the reported non-ergodic behaviour is generic for granular gases with any realistic dependence of epsilon on the impact velocity of particles.},
  language  = {en}
}
@article{ShinCherstvyMetzler2015,
  author    = {Shin, Jaeoh and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Polymer looping is controlled by macromolecular crowding, spatial confinement, and chain stiffness},
  series = {ACS Macro Letters},
  volume    = {4},
  journal   = {ACS Macro Letters},
  number    = {2},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {2161-1653},
  doi       = {10.1021/mz500709w},
  pages     = {202 -- 206},
  year      = {2015},
  abstract  = {We study by extensive computer simulations the looping characteristics of linear polymers with varying persistence length inside a spherical cavity in the presence of macromolecular crowding. For stiff chains, the looping probability and looping time reveal wildly oscillating patterns as functions of the chain length. The effects of crowding differ dramatically for flexible versus stiff polymers. While for flexible chains the looping kinetics is slowed down by the crowders, for stiffer chains the kinetics turns out to be either decreased or facilitated, depending on the polymer length. For severe confinement, the looping kinetics may become strongly facilitated by crowding. Our findings are of broad impact for DNA looping in the crowded and compartmentalized interior of living biological cells.},
  language  = {en}
}
@article{GodecMetzler2015,
  author    = {Godec, Aljaz and Metzler, Ralf},
  title     = {Optimization and universality of Brownian search in a basic model of quenched heterogeneous media},
  series = {Physical review : E, Statistical, nonlinear and soft matter physics},
  volume    = {91},
  journal   = {Physical review : E, Statistical, nonlinear and soft matter physics},
  number    = {5},
  publisher = {American Physical Society},
  address   = {College Park},
  issn      = {1539-3755},
  doi       = {10.1103/PhysRevE.91.052134},
  pages     = {17},
  year      = {2015},
  abstract  = {The kinetics of a variety of transport-controlled processes can be reduced to the problem of determining the mean time needed to arrive at a given location for the first time, the so-called mean first-passage time ( MFPT) problem. The occurrence of occasional large jumps or intermittent patterns combining various types of motion are known to outperform the standard random walk with respect to the MFPT, by reducing oversampling of space. Here we show that a regular but spatially heterogeneous random walk can significantly and universally enhance the search in any spatial dimension. In a generic minimal model we consider a spherically symmetric system comprising two concentric regions with piecewise constant diffusivity. The MFPT is analyzed under the constraint of conserved average dynamics, that is, the spatially averaged diffusivity is kept constant. Our analytical calculations and extensive numerical simulations demonstrate the existence of an optimal heterogeneity minimizing the MFPT to the target. We prove that the MFPT for a random walk is completely dominated by what we term direct trajectories towards the target and reveal a remarkable universality of the spatially heterogeneous search with respect to target size and system dimensionality. In contrast to intermittent strategies, which are most profitable in low spatial dimensions, the spatially inhomogeneous search performs best in higher dimensions. Discussing our results alongside recent experiments on single-particle tracking in living cells, we argue that the observed spatial heterogeneity may be beneficial for cellular signaling processes.},
  language  = {en}
}
@article{GhoshCherstvyMetzler2015,
  author    = {Ghosh, Surya K. and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Non-universal tracer diffusion in crowded media of non-inert obstacles},
  series = {Physical chemistry, chemical physics : a journal of European Chemical Societies},
  volume    = {17},
  journal   = {Physical chemistry, chemical physics : a journal of European Chemical Societies},
  number    = {3},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1463-9076},
  doi       = {10.1039/c4cp03599b},
  pages     = {1847 -- 1858},
  year      = {2015},
  abstract  = {We study the diffusion of a tracer particle, which moves in continuum space between a lattice of excluded volume, immobile non-inert obstacles. In particular, we analyse how the strength of the tracer-obstacle interactions and the volume occupancy of the crowders alter the diffusive motion of the tracer. From the details of partitioning of the tracer diffusion modes between trapping states when bound to obstacles and bulk diffusion, we examine the degree of localisation of the tracer in the lattice of crowders. We study the properties of the tracer diffusion in terms of the ensemble and time averaged mean squared displacements, the trapping time distributions, the amplitude variation of the time averaged mean squared displacements, and the non-Gaussianity parameter of the diffusing tracer. We conclude that tracer-obstacle adsorption and binding triggers a transient anomalous diffusion. From a very narrow spread of recorded individual time averaged trajectories we exclude continuous type random walk processes as the underlying physical model of the tracer diffusion in our system. For moderate tracer-crowder attraction the motion is found to be fully ergodic, while at stronger attraction strength a transient disparity between ensemble and time averaged mean squared displacements occurs. We also put our results into perspective with findings from experimental single-particle tracking and simulations of the diffusion of tagged tracers in dense crowded suspensions. Our results have implications for the diffusion, transport, and spreading of chemical components in highly crowded environments inside living cells and other structured liquids.},
  language  = {en}
}
@article{ShinCherstvyMetzler2015,
  author    = {Shin, Jaeoh and Cherstvy, Andrey G. and Metzler, Ralf},
  title     = {Kinetics of polymer looping with macromolecular crowding: effects of volume fraction and crowder size},
  series = {Soft matter},
  volume    = {11},
  journal   = {Soft matter},
  number    = {3},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1744-683X},
  doi       = {10.1039/c4sm02007c},
  pages     = {472 -- 488},
  year      = {2015},
  abstract  = {The looping of polymers such as DNA is a fundamental process in the molecular biology of living cells, whose interior is characterised by a high degree of molecular crowding. We here investigate in detail the looping dynamics of flexible polymer chains in the presence of different degrees of crowding. From the analysis of the looping-unlooping rates and the looping probabilities of the chain ends we show that the presence of small crowders typically slows down the chain dynamics but larger crowders may in fact facilitate the looping. We rationalise these non-trivial and often counterintuitive effects of the crowder size on the looping kinetics in terms of an effective solution viscosity and standard excluded volume. It is shown that for small crowders the effect of an increased viscosity dominates, while for big crowders we argue that confinement effects (caging) prevail. The tradeoff between both trends can thus result in the impediment or facilitation of polymer looping, depending on the crowder size. We also examine how the crowding volume fraction, chain length, and the attraction strength of the contact groups of the polymer chain affect the looping kinetics and hairpin formation dynamics. Our results are relevant for DNA looping in the absence and presence of protein mediation, DNA hairpin formation, RNA folding, and the folding of polypeptide chains under biologically relevant high-crowding conditions.},
  language  = {en}
}
@article{deCarvalhoMetzlerCherstvy2015,
  author    = {de Carvalho, Sidney J. and Metzler, Ralf and Cherstvy, Andrey G.},
  title     = {Inverted critical adsorption of polyelectrolytes in confinement},
  series = {Soft matter},
  journal   = {Soft matter},
  number    = {11},
  publisher = {Royal Society of Chemistry},
  address   = {London},
  issn      = {1744-6848},
  doi       = {10.1039/C5SM00635J},
  pages     = {4430 -- 4443},
  year      = {2015},
  abstract  = {What are the fundamental laws for the adsorption of charged polymers onto oppositely charged surfaces, for convex, planar, and concave geometries? This question is at the heart of surface coating applications, various complex formation phenomena, as well as in the context of cellular and viral biophysics. It has been a long-standing challenge in theoretical polymer physics; for realistic systems the quantitative understanding is however often achievable only by computer simulations. In this study, we present the findings of such extensive Monte-Carlo in silico experiments for polymer-surface adsorption in confined domains. We study the inverted critical adsorption of finite-length polyelectrolytes in three fundamental geometries: planar slit, cylindrical pore, and spherical cavity. The scaling relations extracted from simulations for the critical surface charge density sc—defining the adsorption-desorption transition—are in excellent agreement with our analytical calculations based on the ground-state analysis of the Edwards equation. In particular, we confirm the magnitude and scaling of sc for the concave interfaces versus the Debye screening length 1/k and the extent of confinement a for these three interfaces for small ka values. For large ka the critical adsorption condition approaches the known planar limit. The transition between the two regimes takes place when the radius of surface curvature or half of the slit thickness a is of the order of 1/k. We also rationalize how sc(k) dependence gets modified for semi-flexible versus flexible chains under external confinement. We examine the implications of the chain length for critical adsorption—the effect often hard to tackle theoretically—putting an emphasis on polymers inside attractive spherical cavities. The applications of our findings to some biological systems are discussed, for instance the adsorption of nucleic acids onto the inner surfaces of cylindrical and spherical viral capsids.},
  language  = {en}
}