Fabio Cecconi

Topological thermal instability and length of proteins

We present an analysis of the effects of global topology on the structural stability of folded proteins in thermal equilibrium with a heat bath. For a large class of single domain proteins, we computed the harmonic spectrum within the Gaussian Network Model (GNM) and determined their spectral dimension, a parameter describing the low frequency behavior of the density of modes. We found a surprisingly strong correlation between the spectral dimension and the number of amino acids in the protein. Considering that larger spectral dimension values relate to more topologically compact folded states, our results indicate that, for a given temperature and length of protein, the folded structure corresponds to a less compact folding, one compatible with thermodynamic stability. Proteins 2004.

Molecular Dynamics Studies on HIV-1 Protease: Drug Resistance and Folding Pathways.

Drug resistance to HIV‐1 protease involves the accumulation of multiple mutations in the protein. We investigate the role of these mutations by using molecular dynamics simulations that exploit the influence of the native‐state topology in the folding process. Our calculations show that sites contributing to phenotypic resistance of FDA‐approved drugs are among the most sensitive positions for the stability of partially folded states and should play a relevant role in the folding process. Furthermore, associations between amino acid sites mutating under drug treatment are shown to be statistically correlated. The striking correlation between clinical data and our calculations suggest a novel approach to the design of drugs tailored to bind regions crucial not only for protein function, but for folding as well. Proteins 2001;43:365–372.

Fluid-like behavior of a one-dimensional granular gas

We study the properties of a one-dimensional (1D) granular gas consisting of N hard rods on a line of length L (with periodic boundary conditions). The particles collide inelastically and are fluidized by a heat bath at temperature Tb and viscosity gamma. The analysis is supported by molecular dynamics simulations. The average properties of the system are first discussed, focusing on the relations between granular temperature Tg=mv2, kinetic pressure, and density rho=N/L. Thereafter, we consider the fluctuations around the average behavior obtaining a slightly non-Gaussian behavior of the velocity distributions and a spatially correlated velocity field; the density field displays clustering: this is reflected in the structure factor which has a peak in the k approximately 0 region suggesting an analogy between inelastic hard core interactions and an effective attractive potential. Finally, we study the transport properties, showing the typical subdiffusive behavior of 1D stochastically driven systems, i.e., approximately Dt(1/2), where D for the inelastic fluid is larger than the elastic case. This is directly related to the peak of the structure factor at small wave vectors.

Theory of thermostatted inhomogeneous granular fluids: a self-consistent density functional description.

The authors present a study of the nonequilibrium statistical properties of a one dimensional hard-rod fluid dissipating energy via inelastic collisions and subject to the action of a Gaussian heat bath, simulating an external driving mechanism. They show that the description of the fluid based on the one-particle phase-space reduced distribution function, in principle necessary because of the presence of velocity dependent collisional dissipation, can be contracted to a simpler description in configurational space. Indeed, by means of a multiple-time-scale method the authors derive a self-consistent governing equation for the particle density distribution function. This equation is similar to the dynamic density functional equation employed in the study of colloids, but contains additional terms taking into account the inelastic nature of the fluid. Such terms cannot be derived from a Liapunov generating functional and contribute not only to the relaxational properties, but also to the nonequilibrium steady state properties. A validation of the theory against molecular dynamics simulations is presented in a series of cases, and good agreement is found.

A Statistical Model for Translocation of Structured Polypeptide Chains through Nanopores

The translocation process of a globular protein (ubiquitin) across a cylindrical nanopore is studied via molecular dynamics simulations. The ubiquitin is described by a native-centric model on a Calpha carbon backbone to investigate the influence of protein-like structural properties on the translocation mechanism. A thermodynamical and kinetic characterization of the process is obtained by studying the statistics of blockage times, the mobility, and the translocation probability as a function of the pulling force F acting in the pore. The transport dynamics occurs when the force exceeds a threshold Fc depending on a free-energy barrier that ubiquitin has to overcome in order to slide along the channel. Such a barrier results from competition of the unfolding energy and the entropy associated with the confinement effects of the pore. We implement appropriate umbrella sampling simulations to compute the free-energy profile as a function of the position of the ubiquitin center of mass inside of the channel (reaction coordinate). This free energy is then used to construct a phenomenological drift-diffusion model in the reaction coordinate which explains and reproduces the behavior of the observables during the translocation.

Brownian motion and diffusion: From stochastic processes to chaos and beyond

One century after Einsteins work, Brownian motion still remains both a fundamental open issue and a continuous source of inspiration for many areas of natural sciences. We first present a discussion about stochastic and deterministic approaches proposed in the literature to model the Brownian motion and more general diffusive behaviors. Then, we focus on the problems concerning the determination of the microscopic nature of diffusion by means of data analysis. Finally, we discuss the general conditions required for the onset of large scale diffusive motion.

Multistep Current Signal in Protein Translocation through Graphene Nanopores

In nanopore sensing experiments, the properties of molecules are probed by the variation of ionic currents flowing through the nanopore. In this context, the electronic properties and the single-layer thickness of graphene constitute a major advantage for molecule characterization. Here we analyze the translocation pathway of the thioredoxin protein across a graphene nanopore, and the related ionic currents, by integrating two nonequilibrium molecular dynamics methods with a bioinformatic structural analysis. To obtain a qualitative picture of the translocation process and to identify salient features we performed unsupervised structural clustering on translocation conformations. This allowed us to identify some specific and robust translocation intermediates, characterized by significantly different ionic current flows. We found that the ion current strictly anticorrelates with the amount of pore occupancy by thioredoxin residues, providing a putative explanation of the multilevel current scenario observed in recently published translocation experiments.

The origin of diffusion: the case of non-chaotic systems

Abstract We investigate the origin of diffusion in non-chaotic systems. As an example, we consider 1D map models whose slope is everywhere 1 (therefore the Lyapunov exponent is zero) but with random quenched discontinuities and quasi-periodic forcing. The models are constructed as non-chaotic approximations of chaotic maps showing deterministic diffusion, and represent one-dimensional versions of a Lorentz gas with polygonal obstacles (e.g., the Ehrenfest wind-tree model). In particular, a simple construction shows that these maps define non-chaotic billiards in space–time. The models exhibit, in a wide range of the parameters, the same diffusive behavior of the corresponding chaotic versions. We present evidence of two sufficient ingredients for diffusive behavior in one-dimensional, non-chaotic systems: (i) a finite size, algebraic instability mechanism; (ii) a mechanism that suppresses periodic orbits.

Crucial stages of protein folding through a solvable model: Predicting target sites for enzyme-inhibiting drugs

An exactly solvable model based on the topology of a protein native state is applied to identify bottlenecks and key sites for the folding of human immunodeficiency virus type 1 (HIV‐1) protease. The predicted sites are found to correlate well with clinical data on resistance to Food and Drug Administration‐approved drugs. It has been observed that the effects of drug therapy are to induce multiple mutations on the protease. The sites where such mutations occur correlate well with those involved in folding bottlenecks identified through the deterministic procedure proposed in this study. The high statistical significance of the observed correlations suggests that the approach may be promisingly used in conjunction with traditional techniques to identify candidate locations for drug attacks.

Role of denaturation in maltose binding protein translocation dynamics.

We present a computational study on the driven transport of the Maltose Binding Protein (MBP) across nanochannels in the framework of coarse-grained modeling. The work is motivated by recent experiments on voltage-driven transport of MBP across nanopores exploring the influence of denaturation on translocation pathways. Our simplified approach allows a statistical mechanical interpretation of the process which may be convenient also to the experiments. Specifically, we identify and characterize short and long channel blockades, associated to the translocation of denaturated and folded MBP conformations, respectively. We show that long blockades are related to long stall events where MBP undergoes specific and reproducible structural rearrangements. To clarify the origin of the stalls, the stick-and-slip translocation is compared to mechanical unfolding pathways obtained via steered molecular dynamics. This comparison clearly shows the translocation pathway to significantly differ from free-space unfolding dynamics and strongly suggests that stalling events are preferentially determined by the MBP regions with higher density of long-range native interactions. This result might constitute a possible criterion to predict a priori some statistical features of protein translocation from the structural analysis.