1,720,994 research outputs found
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
Unveiling the Gating Mechanism of CRAC Channel: A Computational Study
Full text linkCRAC channel is ubiquitous and its importance in the regulation of the immune system is testified by the severe immunodeficiencies caused by its mutations. In this work we took advantage of the availability of open and closed structures of this channel to run for the first time simulations of the whole gating process reaching the relevant time-scale with an enhanced sampling technique, Targeted Molecular Dynamics. Our simulations highlighted a complex allosteric propagation of the conformational change from peripheral helices, where the activator STIM1 binds, to the central pore helices. In agreement with mutagenesis data, our simulations revealed the key role of residue H206 whose displacement creates an empty space behind the hydrophobic region of the pore, thus releasing a steric brake and allowing the opening of the channel. Conversely, the process of pore closing culminates with the formation of a bubble that occludes the pore even in the absence of steric block. This mechanism, known as “hydrophobic gating”, has been observed in an increasing number of biological ion channels and also in artificial nanopores. Our study therefore shows promise not only to better understand the molecular origin of diseases caused by disrupted calcium signaling, but also to clarify the mode of action of hydrophobically gated ion channels, possibly even suggesting strategies for the biomimetic design of synthetic nanopores
Analyzing pathogenic mutations of C5 domain from cardiac myosin binding protein C through MD simulations
Full text linkThe 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
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
Full text linkThe 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
Realistic Worst-Case Modeling by Performance Level Principal Component Analysis
No full textA new algorithm to determine the number and value of realistic worst-case models for the performance of module library components is presented in this paper. The proposed algorithm employs principal components analysis (PCA) at the performance level to identify the main independent sources of variance for the performance of a set of library modules. Response surfaces methodology (RSM) and propagation of variance (POV) based algorithms are used to efficiently compute the performance level covariance matrix and nonlinear maximum likelihood optimization to trace back worst case models at the SPICE level. The effectiveness of the proposed methodology has been demonstrated by determining a realistic set of worst case models for a 0.25 μm CMOS standard cell library
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
Full text linkThere 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
Opening pathways of the DNA clamps proliferating cell nuclear antigen and Rad9-Rad1-Hus1
No full textProliferating cell nuclear antigen and the checkpoint clamp Rad9-Rad1-Hus1 topologically encircle DNA and act as mobile platforms in the recruitment of proteins involved in DNA damage response and cell cycle regulation. To fulfill these vital cellular functions, both clamps need to be opened and loaded onto DNA by a clamp loader complex- A process, which involves disruption of the DNA clamp's subunit interfaces. Herein, we compare the relative stabilities of the interfaces using the molecular mechanics Poisson-Boltzmann solvent accessible surface method. We identify the Rad9-Rad1 interface as the weakest and, therefore, most likely to open during clamp loading. We also delineate the dominant interface disruption pathways under external forces in multiple-trajectory steered molecular dynamics runs. We show that, similar to the case of protein folding, clamp opening may not proceed through a single interface breakdown mechanism. Instead, we identify an ensemble of opening pathways, some more prevalent than others, characterized by specific groups of contacts that differentially stabilize the regions of the interface and determine the spatial and temporal patterns of breakdown. In Rad9-Rad1-Hus1, the Rad9-Rad1 and Rad9-Hus1 interfaces share the same dominant unzipping pathway, whereas the Hus1-Rad1 interface is disrupted concertedly with no preferred directionality. © 2013 The Author(s)
Impact of Unrealistic Worst-Case Modelling on the Performance of VLSI Circuits in Deep Sub-Micron CMOS Technologies
No full textThe impact of process fluctuations on the variability of deep sub-micron (DSM) VLSI circuit performances is investigated in this paper. In particular, we show that, as process dimensions scale down in the sub half-micron region, the relative weight of process variability tends to increase, thus wearing down a nonnegligible portion of the benefits that are expected from minimum feature size scaling. Therefore, in order to better exploit the advance of process technology, it is essential to adopt a realistic approach to worst case modeling, as in the assigned probability technique (APT) (Dal Fabbro et al, Proc. 32nd ACM/IEEE Design Automation Conf., pp. 702-6, 1995). The application of the APT technique to a 16-bit ripple-carry adder designed in 0.35 μm, 0.25 μm and 0.18 μm CMOS technologies with a power supply ranging from 3.3 V down to 1 V demonstrates how the manufacturability of DSM designs is going to be a vital factor for the successful implementation of high performance or low-power systems in 0.18 μm and lesser technologies
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