Stefano Luccioli

Changing the Mechanical Unfolding Pathway of FnIII10 by Tuning the Pulling Strength

We investigate the mechanical unfolding of the tenth type III domain from fibronectin (FnIII(10)) both at constant force and at constant pulling velocity, by all-atom Monte Carlo simulations. We observe both apparent two-state unfolding and several unfolding pathways involving one of three major, mutually exclusive intermediate states. All three major intermediates lack two of seven native beta-strands, and share a quite similar extension. The unfolding behavior is found to depend strongly on the pulling conditions. In particular, we observe large variations in the relative frequencies of occurrence for the intermediates. At low constant force or low constant velocity, all three major intermediates occur with a significant frequency. At high constant force or high constant velocity, one of them, with the N- and C-terminal beta-strands detached, dominates over the other two. Using the extended Jarzynski equality, we also estimate the equilibrium free-energy landscape, calculated as a function of chain extension. The application of a constant pulling force leads to a free-energy profile with three major local minima. Two of these correspond to the native and fully unfolded states, respectively, whereas the third one can be associated with the major unfolding intermediates.

Irregular Collective Behavior of Heterogeneous Neural Networks

We investigate a network of integrate-and-fire neurons characterized by a distribution of spiking frequencies. Upon increasing the coupling strength, the model exhibits a transition from an asynchronous regime to a nontrivial collective behavior. Numerical simulations of large systems indicate that, at variance with the Kuramoto model, (i) the macroscopic dynamics stays irregular and (ii) the microscopic (single-neuron) evolution is linearly stable.

Collective dynamics in sparse networks.

The microscopic and macroscopic dynamics of random networks is investigated in the strong-dilution limit (i.e., for sparse networks). By simulating chaotic maps, Stuart-Landau oscillators, and leaky integrate-and-fire neurons, we show that a finite connectivity (of the order of a few tens) is able to sustain a nontrivial collective dynamics even in the thermodynamic limit. Although the network structure implies a nonadditive dynamics, the microscopic evolution is extensive (i.e., the number of active degrees of freedom is proportional to the number of network elements).

Double coherence resonance in neuron models driven by discrete correlated noise.

We study the influence of correlations among discrete stochastic excitatory or inhibitory inputs on the response of the FitzHugh-Nagumo neuron model. For any level of correlation, the emitted signal exhibits at some finite noise intensity a maximal degree of regularity, i.e., a coherence resonance. Furthermore, for either inhibitory or excitatory correlated stimuli, a double coherence resonance is observable. Double coherence resonance refers to a (absolute) maximum coherence in the output occurring for an optimal combination of noise variance and correlation. All of these effects can be explained by taking advantage of the discrete nature of the correlated inputs.

Clique of functional hubs orchestrates population bursts in developmentally regulated neural networks

It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity.

Discrete breathers in a realistic coarse-grained model of proteins

We report the results of molecular dynamics simulations of an off-lattice protein model featuring a physical force-field and amino-acid sequence. We show that localized modes of nonlinear origin, discrete breathers (DBs), emerge naturally as continuations of a subset of high-frequency normal modes residing at specific sites dictated by the native fold. DBs are time-periodic, space-localized vibrational modes that exist generically in nonlinear discrete systems and are known for their resilience and ability to concentrate energy for long times. In the case of the small β-barrel structure that we consider, DB-mediated localization occurs on the turns connecting the strands. At high energies, DBs stabilize the structure by concentrating energy on a few sites, while their collapse marks the onset of large-amplitude fluctuations of the protein. Furthermore, we show how breathers develop as energy-accumulating centres following perturbations even at distant locations, thus mediating efficient and irreversible energy transfers. Remarkably, due to the presence of angular potentials, the breather induces a local static distortion of the native fold. Altogether, the combination of these two nonlinear effects may provide a ready means for remotely controlling local conformational changes in proteins.

Unfolding times for proteins in a force clamp

The escape process from the native valley for proteins subjected to a constant stretching force is examined using a model for a beta barrel. For a wide range of forces, the unfolding dynamics can be treated as one-dimensional diffusion, parametrized in terms of the end-to-end distance. In particular, the escape times can be evaluated as first passage times for a Brownian particle moving on the protein free-energy landscape, using the Smoluchowski equation. At strong forces, the unfolding process can be viewed as a diffusive drift away from the native state, while at weak forces thermal activation is the relevant mechanism. An escape-time analysis within this approach reveals a crossover from an exponential to an inverse Gaussian escape-time distribution upon passing from weak to strong forces. Moreover, a single expression valid at weak and strong forces can be devised both for the average unfolding time as well as for the corresponding variance. The analysis offers a possible explanation of recent experimental findings for the proteins ddFLN4 and ubiquitin.

Dynamical response of the Hodgkin-Huxley model in the high-input regime

The response of the Hodgkin-Huxley neuronal model subjected to stochastic uncorrelated spike trains originating from a large number of inhibitory and excitatory post-synaptic potentials is analyzed in detail. The model is examined in its three fundamental dynamical regimes: silence, bistability, and repetitive firing. Its response is characterized in terms of statistical indicators (interspike-interval distributions and their first moments) as well as of dynamical indicators (autocorrelation functions and conditional entropies). In the silent regime, the coexistence of two different coherence resonances is revealed: one occurs at quite low noise and is related to the stimulation of subthreshold oscillations around the rest state; the second one (at intermediate noise variance) is associated with the regularization of the sequence of spikes emitted by the neuron. Bistability in the low noise limit can be interpreted in terms of jumping processes across barriers activated by stochastic fluctuations. In the repetitive firing regime a maximization of incoherence is observed at finite noise variance. Finally, the mechanisms responsible for the different features appearing in the interspike-interval distributions (like multimodality and exponential tails) are clearly identified in the various regimes.

Coherent response of the Hodgkin-Huxley neuron in the high-input regime

We analyze the response of the Hodgkin-Huxley neuron to a large number of uncorrelated stochastic inhibitory and excitatory post-synaptic spike trains. In order to clarify the various mechanisms responsible for noise-induced spike triggering we examine the model in its silent regime. We report the coexistence of two distinct coherence resonances: the first one at low noise is due to the stimulation of correlated subthreshold oscillations; the second one at intermediate noise variances is instead related to the regularization of the emitted spike trains.

Dynamics of Networks of Leaky-Integrate-and-Fire Neurons

The dynamics of pulse-coupled leaky-integrate-and-fire neurons is discussed in networks with arbitrary structure and in the presence of delayed interactions. The evolution equations are formally recasted as an event-driven map in a general context where the pulses are assumed to have a finite width. The final structure of the mathematical model is simple enough to allow for an easy implementation of standard nonlinear dynamics tools. We also discuss the properties of the transient dynamics in the presence of quenched disorder (and δ-like pulses). We find that the length of the transient depends strongly on the number N of neurons. It can be as long as 106–107 inter-spike intervals for relatively small networks, but it decreases upon increasing N because of the presence of stable clustered states. Finally, we discuss the same problem in the presence of randomly fluctuating synaptic connections (annealed disorder). The stationary state turns out to be strongly affected by finite-size corrections, to the extent that the number of clusters depends on the network size even for N≈20,000.