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Structural biology

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
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
Protein-protein interaction:
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.
  • L. Cavallo, Univ. Salerno