Claude Loverdo

Intermittent search strategies

This review examines intermittent target search strategies, which combine phases of slow motion, allowing the searcher to detect the target, and phases of fast motion during which targets cannot be detected. We first show that intermittent search strategies are actually widely observed at various scales. At the macroscopic scale, this is for example the case of animals looking for food ; at the microscopic scale, intermittent transport patterns are involved in reaction pathway of DNA binding proteins as well as in intracellular transport. Second, we introduce generic stochastic models, which show that intermittent strategies are efficient strategies, which enable to minimize the search time. This suggests that the intrinsic efficiency of intermittent search strategies could justify their frequent observation in nature. Last, beyond these modeling aspects, we propose that intermittent strategies could be used also in a broader context to design and accelerate search processes.

Sliding and jumping of single EcoRV restriction enzymes on non-cognate DNA

The restriction endonuclease EcoRV can rapidly locate a short recognition site within long non-cognate DNA using ‘facilitated diffusion’. This process has long been attributed to a sliding mechanism, in which the enzyme first binds to the DNA via nonspecific interaction and then moves along the DNA by 1D diffusion. Recent studies, however, provided evidence that 3D translocations (hopping/jumping) also help EcoRV to locate its target site. Here we report the first direct observation of sliding and jumping of individual EcoRV molecules along nonspecific DNA. Using fluorescence microscopy, we could distinguish between a slow 1D diffusion of the enzyme and a fast translocation mechanism that was demonstrated to stem from 3D jumps. Salt effects on both sliding and jumping were investigated, and we developed numerical simulations to account for both the jump frequency and the jump length distribution. We deduced from our study the 1D diffusion coefficient of EcoRV, and we estimated the number of jumps occurring during an interaction event with nonspecific DNA. Our results substantiate that sliding alternates with hopping/jumping during the facilitated diffusion of EcoRV and, furthermore, set up a framework for the investigation of target site location by other DNA-binding proteins.

Two-dimensional intermittent search processes: An alternative to Lévy flight strategies.

Lévy flights are known to be optimal search strategies in the particular case of revisitable targets. In the relevant situation of nonrevisitable targets, we propose an alternative model of two-dimensional (2D) search processes, which explicitly relies on the widely observed intermittent behavior of foraging animals. We show analytically that intermittent strategies can minimize the search time, and therefore do constitute real optimal strategies. We study two representative modes of target detection and determine which features of the search time are robust and do not depend on the specific characteristics of detection mechanisms. In particular, both modes lead to a global minimum of the search time as a function of the typical times spent in each state, for the same optimal duration of the ballistic phase. This last quantity could be a universal feature of 2D intermittent search strategies.

A quantitative high-resolution genetic profile rapidly identifies sequence determinants of hepatitis C viral fitness and drug sensitivity.

Widely used chemical genetic screens have greatly facilitated the identification of many antiviral agents. However, the regions of interaction and inhibitory mechanisms of many therapeutic candidates have yet to be elucidated. Previous chemical screens identified Daclatasvir (BMS-790052) as a potent nonstructural protein 5A (NS5A) inhibitor for Hepatitis C virus (HCV) infection with an unclear inhibitory mechanism. Here we have developed a quantitative high-resolution genetic (qHRG) approach to systematically map the drug-protein interactions between Daclatasvir and NS5A and profile genetic barriers to Daclatasvir resistance. We implemented saturation mutagenesis in combination with next-generation sequencing technology to systematically quantify the effect of every possible amino acid substitution in the drug-targeted region (domain IA of NS5A) on replication fitness and sensitivity to Daclatasvir. This enabled determination of the residues governing drug-protein interactions. The relative fitness and drug sensitivity profiles also provide a comprehensive reference of the genetic barriers for all possible single amino acid changes during viral evolution, which we utilized to predict clinical outcomes using mathematical models. We envision that this high-resolution profiling methodology will be useful for next-generation drug development to select drugs with higher fitness costs to resistance, and also for informing the rational use of drugs based on viral variant spectra from patients.

Evidence of anisotropic quenched disorder effects on a smectic liquid crystal confined in porous silicon.

We present a neutron scattering analysis of the structure of the smectic liquid crystal octylcyanobiphenyl (8CB) confined in one-dimensional nanopores of porous silicon films (PS). The smectic transition is completely suppressed, leading to the extension of a short-range ordered smectic phase aligned along the pore axis. It evolves reversibly over an extended temperature range, down to 50 K below the N-SmA transition in pure 8CB. This behavior strongly differs from previous observations of smectics in different one-dimensional porous materials. A coherent picture of this striking behavior requires that quenched disorder effects are invoked. The strongly disordered nature of the inner surface of PS acts as random fields coupling to the smectic order. The one-dimensionality of PS nanochannels offers perspectives on quenched disorder effects, of which observation has been restricted to homogeneous random porous materials so far.

Optimal reaction time for surface-mediated diffusion.

We present an exact calculation of the mean first-passage time to a small target on the surface of a 2D or 3D spherical domain, for a molecule performing surface-mediated diffusion. This minimal model of interfacial reactions, which explicitly takes into account the combination of surface and bulk diffusion, shows the importance of correlations induced by the coupling of the switching dynamics to the geometry of the confinement, ignored so far. Our results show that, in the context of interfacial systems in confinement, the reaction time can be minimized as a function of the desorption rate from the surface, which puts forward a general mechanism of enhancement and regulation of chemical and biological reactivity.

A minimal model of intermittent search in dimension two

We propose and analyse a model of bidimensional search processes, explicitly relying on the widely observed intermittent behaviour of foraging animals, which involves a searcher enjoying minimal orientational and temporal memory skills. We show analytically that, in the case of non-revisitable targets, intermittent strategies can minimize the search time, and therefore constitute real optimal strategies, as opposed to Levy flights strategy which are optimal only in the particular case of revisitable targets. Two representative modes of target detection are presented, and they allow us to determine which characteristics of the optimal strategy are robust and do not depend on the specific characteristics of detection mechanisms. In particular, our study tends to show that the optimal duration of the ballistic phase is a universal feature of bidimensional intermittent search strategies. Last, by comparing the results of our minimal model to systematic search strategies, we show that if temporal and orientational memory skills speed up the search, they do not change the order of magnitude of the search time.

Optimizing intermittent reaction paths

Various examples of biochemical reactions in cells, such as DNA/protein interactions, reveal that in extremely diluted regimes reaction paths are not always simple brownian trajectories. They can rather be qualified as intermittent, since they combine slow diffusion phases on one hand and a second mode of faster transport on the other hand, which can be either a faster diffusion mode, as in the case of DNA-binding proteins, or a ballistic mode powered by molecular motors in the case of intracellular transport. In this article, we introduce simple theoretical models which permit to calculate explicitly the reaction rates for reactions limited by intermittent transport. This approach shows quantitatively that intermittent reaction pathways are actually very efficient, since they permit to significantly increase the reaction rates, which could explain why they are observed so often. Moreover, we give theoretical arguments which suggest that intermittent transport could also be useful for in vitro chemistry. Indeed, we show that intermittent transport naturally pops up in the context of reaction at interfaces, where reactants combine surface diffusion phases and bulk excursions, and could permit to enhance reactivity. In this case, adjusting chemically the affinity of reactants with the interface makes possible to optimize the reaction rate.

Multiple scales of selection influence the evolutionary emergence of novel pathogens

When pathogens encounter a novel environment, such as a new host species or treatment with an antimicrobial drug, their fitness may be reduced so that adaptation is necessary to avoid extinction. Evolutionary emergence is the process by which new pathogen strains arise in response to such selective pressures. Theoretical studies over the last decade have clarified some determinants of emergence risk, but have neglected the influence of fitness on evolutionary rates and have not accounted for the multiple scales at which pathogens must compete successfully. We present a cross-scale theory for evolutionary emergence, which embeds a mechanistic model of within-host selection into a stochastic model for emergence at the population scale. We explore how fitness landscapes at within-host and between-host scales can interact to influence the probability that a pathogen lineage will emerge successfully. Results show that positive correlations between fitnesses across scales can greatly facilitate emergence, while cross-scale conflicts in selection can lead to evolutionary dead ends. The local genotype space of the initial strain of a pathogen can have disproportionate influence on emergence probability. Our cross-scale model represents a step towards integrating laboratory experiments with field surveillance data to create a rational framework to assess emergence risk.

Mean First-Passage Time of Surface-Mediated Diffusion in Spherical Domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.