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Structural biology

Molecular dynamics simulations of DNA nano-structures
DNA DNA represents one of the most efficient building blocks for the creation of predesigned self-assembling nano-structures. Its high thermodynamic stability and its unique self-recognition properties have made this biopolymer an essential material for bio-nanotechnology. Consequently a large variety of precisely programmed 3D DNA nano-structures have been presented and, with the increased knowledge in the use of self-assembling DNA functionality, novel applications in biology are beginning to emerge. In recent years molecular dynamics (MD) atomistic simulations have been successfully used to characterize structure and dynamics of DNA nano-structures. Exploration of the properties of a truncated octahedral DNA nano-cage family has permitted us to show unusual curvature and stacking imposed by the nano-structure that have never been observed in the simulation of short DNA strands. Nowadays nano-biomedicine represents an ambitious target in the use of DNA nano-cage designed for controlled encapsulation, release and cell target-delivery of biomolecules. For this purpose we have presented a structural characterization, carried out through MD simulation, of a temperature controlled encapsulation and release of the horseradish peroxidase enzyme, using a preassembled and covalently closed 3D DNA cage structure as a controllable encapsulation device. In this paper the MD simulation technique was able to finely characterize the opening/closing molecular mechanism. Recently, we have designed a DNA triple helix with a pH dependent switching mechanism. Using accelerated MD (aMD) simulations we have investigated the pH dependent, reversible mechanism triggering the opening/closing of this DNA triple helix, with the purpose to implement this nanoswitch in a complex DNA nanostructure.
  • Mattia Falconi, Federico Iacovelli, Alessandro Desideri, University of Tor Vergata
CardiomiR: a computational resource for the identification and characterization of miRNA with diagnostic value in the prevention of acute myocardial infarction
cardiomir Atherosclerosis is an immuno-inflammatory disease of the arteries characterized by the formation of atherosclerotic plaques causing thickening of intima, the innermost layer of arteries. The instability of atherosclerotic plaques or their eventual rupture may trigger an acute coronary syndrome (ACS), which represents a series of acute myocardial ischemic states including unstable angina (UA) and acute myocardial infarction (AMI). Sadly, despite the mortality rate due to cardiovascular diseases has decreased in recent years, they still represent the worldwide leading cause of death. To date no efficient and accurate prediction system able to assess in advance the risk of AMI has been presented. A large amount of experimental evidences indicates that microRNAs (miRNAs), a class of small non-coding RNAs, are implicated in a wide variety of diseases including cardiovascular ones and IMA. Therefore, circulating miRNAs have been proposed as new bio-diagnostic markers able to discriminate various pathological conditions. Our project is aimed to the development of a Support Vector Machine (SVM), trained with data obtained by applying target prediction algorithms to miRNAs known to be associated with the development of cardiovascular diseases. A web application, able to verify the consistency of miRNAs as a diagnostic bio-markers of AMI, will be designed and implemented through the use of the CRESCO HPC clusters.
  • Mattia Falconi, Federico Iacovelli, University of Tor Vergata
Hybrid MPI/OpenMP Implementation of the ORAC Molecular Dynamics Program for Generalized Ensemble and Fast Switching Alchemical Simulations
We present a new release of the ORAC program with a hybrid OpenMP/MPI parallelism tailored for generalized ensemble (GE) and fast switching double annihilation (FS-DAM) nonequilibrium technology aimed at evaluating the binding free energy in drug-receptor system on high performance computing platforms. The production of the GE or FS-DAM trajectories is handled using a weak scaling parallel approach on the MPI level only, while a strong scaling force decomposition scheme is implemented for intranode computations with shared memory access at the OpenMP level. The efficiency, simplicity, and inherent parallel nature of the ORAC implementation of the FS-DAM algorithm, project the code as a possible effective tool for a second generation high throughput virtual screening in drug discovery and design. The code, along with documentation, testing, and ancillary tools, is distributed under the provisions of the General Public License and can be freely downloaded at www.chim.unifi.it/orac.
  • Piero Procacci, University of Florence
Self-Assembly of Triton X-100 in Water Solutions: A Multiscale Simulation Study Linking Mesoscale to Atomistic Models
vlp A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent widely employed in biology. The hybrid particle field formulation of the model allows simulations of large-scale systems. The coarse-grained (CG) model, accurately validated in a wide range of concentrations, shows a critical micelle concentration, shape transition in isotropic micellar phase, and appearance of hexagonal ordered phase in the experimental ranges reported in the literature. The fine resolution of the proposed CG model allows one to obtain, by a suitable reverse mapping procedure, atomistic models of micellar assemblies and of the hexagonal phase. In particular, atomistic models of the micelles give structures in good agreement with experimental pair distance distribution functions and hydrodynamic measurements. The picture emerging by detailed analysis of simulated systems is quite complex. Polydisperse mixtures of spherical-, oblate-, and prolate-shaped aggregates have been found. The shape and the micelle behavior are mainly dictated by the aggregation number (Nagg). Micelles with low Nagg values are spherical, while those with high Nagg values are characterized by prolate ellipsoidal shapes. For intermediate Nagg values fluxional micelles alternating between oblate and prolate shapes are found. The proposed model opens the way to investigations of several mechanisms involving TX-100 assembly in protein and membrane biophysics.
  • A. De Nicola, G. Milano, University of Salerno
  • C. Rosano, M. Rocco, Istituto Nazionale per la Ricerca sul Cranco, Genova
  • T. Kawakatsu, Tohoku University, Japan
  • M. Celino, ENEA
Virus-like particles
vlp Virus-like particles (VLPs) are composed of viral structural proteins that retain the ability to self-assemble without the presence of the encoding viral genome. VLPs and viruses share high versatility, propensity to form arrays and high programmability through genetic engineering. For these reasons they have recently emerged as platforms for synthetic manipulation with a range of applications from materials science to medicine.
  • Caterina Arcangeli, ENEA
Molecular dynamics simulations to study the structural features of a thermophilic protein
Marabotti The computational activity described in this report is part of a broader work devoted to the molecular characterization of a maltotriose-binding protein (MalE2) from the thermophilic organism Thermus thermophilus. In the complete work, data from molecular dynamics (MD) simulations were combined to data from fluorescence correlation spectroscopy in order to acquire structural information on the pH-induced unfolding of this protein. Data obtained were useful in order to evaluate the structural properties of this protein, for its possible use as biological counterpart of a developing biosensor. It was also interesting to match data obtained with two techniques (computational and experimental) both focused on the study of a single molecule, but with very different timescales (microseconds in the case of fluorescence correlation spectroscopy, nanoseconds in the case of MD simulations).
  • A. Marabotti, Univ Salerno
Actin-actinin complex in mechanosensing
Actine Actinin is a microfilament protein. Alpha-Actinin is a cross-linking protein necessary for the attachment of actin filaments to the Z-lines in skeletal muscle cells, and to the dense bodies in smooth muscle cells. The functional protein is an anti-parallel dimer, which cross-links the thin filaments in adjacent sarcomeres, and therefore coordinated contractions between sarcomeres in the horizontal axis. Both ends of the alpha-Actinin terminals are composed of two calmodulin (CH1 CH2) attached to one monomer, and an EF-domain attached to the antiparallel monomer. We investigate, by means of combined rigid-docking and molecular mechanics, the complex structure of alpha-actinin attached to actin filaments. For the first model we obtained rigidly docked structures of the closed CH1-CH2 conformation to an actin monomer, which was then relaxed in physiologic water. The second and third models consists of an actin trimer or pentamer, representing a fragment of an actin filament in the Holmes configuration. We performed rigid docking of the alpha-actinin CH1-CH2 terminal on the actin fragments, and studied the differential adhesion free energy. The image shows the terminal fragment of alpha-Actinin (pink ribbons) interacting with the actin trimer (white). ATP molecules are also shown in the DB site of each actin monomer.
  • Fabrizio Cleri, Univ. Lille, France
Computational analysis of media effects on model compound MBET-306
Small-molecule inhibitors of Tumor Necrosis factor alpha Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on Hamiltonian Replica Exchange Molecular dynamics simulations of a new compound, named MBET-306, that represents the common scaffold of a family of recently discovered tartrate-based TACE inhibitors. In a previous study we suggested the possibility of a two-stage docking mechanism whereby the formation of an intermediate between the drug in a compact conformation and the catalytic Zinc ion, is followed by a structural rearrangement to an extended conformation favored by the local amphiphilic environment. Our simulations in different solvents show that MBET-306, similar to the parental tartrate compounds, responds to a moderately hydrophobic environment with an increase of the fraction of extended conformations, confirming to be a good model compound of tartrate-derived TACE inhibitors. While the experimental characterization of the compound is still underway in our lab, these results already bode well for a systematic use of MBET-306 as a basic building block for the rational design and synthesis of more complex tartrate-derived TACE inhibitors.
  • C. Guardiania and P. Procacci, Univ Florence
Fluoride Riboswitch Recognition Site using Ab Initio Molecular Dynamics
Fluoride Molecular docking is a fundamental process in biological environment. Among the others we can characterize the action of external agents on immune system. Celiac desease is produced by the strong interaction of a certain class of proteins. Understanding how they interact and how to modify them could give indications for new medical treatments.
  • R. Credentino, L. Cavallo, King Abdullah University of Science and Technology, Kingdom of Saudi Arabia

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