86,597 research outputs found
Analyzing pathogenic mutations of C5 domain from cardiac myosin binding protein C through MD simulations
No full textThe folding properties of wild type and mutants of domain C5 from cardiac myosin binding protein C have been investigated via molecular dynamics simulations within the framework of a native-centric and coarse-grained model. The relevance of a mutation has been assessed through the shift in the unfolding temperature, the change in the unfolding rate it determines and Phi-values analysis. In a previous paper (Guardiani et al. Biophys J 94:1403-1411, 2008), we performed Kinetic simulations on native contact formation revealing an entropy-driven folding pathway originating near the FG and DE loops. This folding mechanism allowed also a possible interpretation of the molecular impact of the three mutations, Arg14His, Arg28His and Asn115Lys involved in the Familial Hypertrophic Cardiomyopathy. Here we extend that analysis by enriching the mutant pool and we identify a correlation between unfolding rates and the number of native contacts retained in the transition state. © 2008 EBSA
A microscopic model of evolution of recombination
No full textWe study the evolution of recombination using a microscopic model developed within the frame of the theory of quantitative traits. Two components of fitness are considered: a static one that describes adaptation to environmental factors not related to the population itself, and a dynamic one that accounts for interactions between organisms, e.g. competition. We focus on the dynamics of colonization of an empty niche. As competition is a function of the population, selection pressure rapidly changes in time. The simulations show that both in the case of flat and steep static fitness landscapes, recombination provides a high velocity of movement in the phenotypic space thus allowing recombinants to colonize the highest fitness regions earlier than non-recombinants that are often driven to extinction. The stabilizing effects of competition and assortativity are also discussed. Finally, the analysis of phase diagrams shows that competition is the key factor for the evolution of recombination, while assortativity plays a significant role only in small populations. © 2004 Published by Elsevier B.V
Attualità di McLuhan
No full textLe teorie del canadese Marshall McLuhan costituiscono tuttora la migliore introduzione ai caratteri tipici della nostra epoca, dominata dalla diffusione delle vie di comunicazione assicurate dall'elettronica. In proposito si può parlare di una Galassia elettronica che fa seguito a quella che proprio McLuhan aveva definito a suo tempo Galassia Gutenberg. L'eta delle macchine, pesanti, stanziali. contro l'età della interconnessione attraverso la rete di tutto con tutto, ovvero di quello che sempre lo studioso canadese ha definito "villaggio globale"
Computational analysis of folding and mutation properties of C5 domain of myosin binding protein C
No full textThermal folding molecular dynamics simulations of the domain C5 of Myosin binding protein C were performed using a native-centric model to study the role of three mutations related to Familial Hypertrophic Cardiomyopathy. Mutation of Asn755 causes the largest shift of the folding temperature, and the residue is located in the CFGA′ β-sheet featuring the highest Φ-values. The mutation thus appears to reduce the thermodynamic stability in agreement with experimental data. The mutations on Arg654 and Arg668, conversely, cause little change in the folding temperature and they reside in the low Φ-value BDE β-sheet, so that their pathological role cannot be related to impairment of the folding process but possibly to the binding with target molecules. As the typical signature of Domain C5 is the presence of a longer and destibilizing CD-loop with respect to the other Ig-like domains, we completed the work with a bioinformatic analysis of this loop showing a high density of negative charge and low hydrophobicity. This indicates the CD-loop as a natively unfolded sequence with a likely coupling between folding and ligand binding. Proteins 2008; 70:1313-1322. © 2007 Wiley-Liss, Inc
Exploring Kv1.2 channel inactivation through MD simulations and network analysis
No full textThe KCNA2 gene encodes the Kv1.2 channel, a mammalian Shaker-like voltage-gated K+ channel, whose defections are linked to neuronal deficiency and childhood epilepsy. Despite the important role in the kinetic behavior of the channel, the inactivation remained hereby elusive. Here, we studied the Kv1.2 inactivation via a combined simulation/network theoretical approach that revealed two distinct pathways coupling the Voltage Sensor Domain and the Pore Domain to the Selectivity Filter. Additionally, we mutated some residues implicated in these paths and we explained microscopically their function in the inactivation mechanism by computing a contact map. Interestingly, some pathological residues shown to impair the inactivation lay on the paths. In summary, the presented results suggest two pathways as the possible molecular basis of the inactivation mechanism in the Kv1.2 channel. These pathways are consistent with earlier mutational studies and known mutations involved in neuronal channelopathies
Coarse grained modeling and approaches to protein folding
No full textThe theoretical prediction of protein structures has become a field of increasing importance in both biology and physics. Reliable prediction methods in fact, would spare time consuming experimental X-ray and NMR techniques and they would represent a challenge for computational protein modeling as well. The well known limitations of all-atom models call for the development of coarse-grained protein descriptions including a minimal number of protein-like features, while being capable of mimicking the essence of protein folding mechanisms. In this paper we review the most important classes of coarse-grained protein models in order of increasing complexity, starting from (over simplified) binary models, to models with one or two reaction centers per residue. We discuss how, despite their simplification, coarsegrained models constitute a viable approach to structure prediction and they shed light on many aspects of protein-folding problem. © 2010 Bentham Science Publishers Ltd
Coarse-grained modeling of protein unspecifically bound to DNA
No full textThere is now a certain consensus that transcription factors (TFs) reach their target sites, where they regulate gene transcription, via a mechanism dubbed facilitated diffusion (FD). In FD, the TF cycles between events of 3D diffusion in solution (jumps), 1D diffusion along DNA (sliding), and small jumps (hopping), achieving association rates higher than for 3D diffusion alone. We investigate the FD phenomenology through molecular dynamics simulations in the framework of coarse-grained modeling. We show that, despite the crude approximations, the model generates, upon varying the equilibrium distance of the DNA-TF interaction, a phenomenology matching a number of experimental and numerical results obtained with more refined models. In particular, focusing on the kinematics of the process, we characterize the geometrical properties of TF trajectories during sliding. We find that sliding occurs via helical paths around the DNA helix, leading to a coupling of translation along the DNA axis with rotation around it. The 1D diffusion constant measured in simulations is found to be interwoven with the geometrical properties of sliding and we develop a simple argument that can be used to quantitatively reproduce the measured values. © 2014 IOP Publishing Ltd
Goffredo Parise and the Orient: a continuous fascination for alterity
No full textThe article deals with the dialogue between Italy and China in Goffredo Parise’s work. It shows that Parises’s deep contact with the oriental cultures changed his narrative process through new stylistic devices and methodological tools. Drawing on the work of the French philosopher and sinologist François Jullien about the logos and the principle of non-contradiction, as well as efficacy and action versus transformation, the article demonstrates that Chinese and Japanese journeys mark a crucial moment for Parise’s activity as journalist (Dear China, 1966 and Elegance is frigid, 1982) as well as author of short stories (Solitudes, 1972-1982)
Integrated approach including docking, MD simulations, and network analysis highlights the action mechanism of the cardiac hERG activator RPR260243
No full texthERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation
The integration of morphological design and topology optimization to enhance the visual quality of electricity pylons
No full textPurpose: This paper aims to enhance the visual quality of artificial above-ground structures, like pylons, masts, and towers of infrastructures and facilities, through a systematic design method for their morphological and structural optimization. Design/methodology/approach: The method achieves the functional and aesthetic goals based on the application of computer-aided tools. In particular, this is achieved according to three key steps: • Morphological development of landscape-related symbolism, environment, or culture and social needs. • Topology optimization of the design concept to reduce the structural weight and its visual impact. • Engineering of the resulting optimized structure. Practical implications: As a case study, the method is used for designing electricity pylons for the coastal territory of a Mediterranean European country, such as Italy. Citizens were involved during the identification phase of a symbolic shape for the concept development and during the final assessment phase. Research limitations/implications: The engineering phase has been performed by assembling standard lattice components with welded connections. Even if the use of this truss-like structure should lead to a minimum cost, the developed structure employs an additional 15%–20% of trusses and sheet metal covers the final cost is higher than a standard lattice pylon. Findings: The result is a structure with enhanced visual quality according to the international guidelines and fully complying with mandatory and functional requirements, such as regulatory and industrial feasibility, as well as those arising from social components. Originality/value: The method shows its potential in defining a custom design for lightweight structures with enhanced visual quality regarding the critical situation discussed here. The method considers both the subjective perception of citizens and their priorities and the landscape where the structures will be installed
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