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Chillemi G.,Interuniversities Consortium for Supercomputing Applications | Coletta A.,University of Rome Tor Vergata | Mancini G.,Interuniversities Consortium for Supercomputing Applications | Sanna N.,Interuniversities Consortium for Supercomputing Applications | Desideri A.,University of Rome Tor Vergata
Theoretical Chemistry Accounts | Year: 2010

A molecular mechanics (MM) force field has been developed for the topotecan (TPT) molecule, an anticancer drug the only molecular target of which is the human topoisomerase I-DNA covalent complex. We proceeded according to the amber03 force field parametrization protocol, based on quantum mechanical calculations with solvent effects included by means of continuum models. An adequate description of the electronic states of TPT has been ensured comparing calculated IR vibrational frequencies and NMR chemical shifts with experimental results. Bonded molecular parameters have been verified by comparison with ab initio normal mode vibrational analysis, while atomic charges have been fitted either using the restrained electrostatic potential fitting (RESP) or the multi-conformational RESP (MultiRESP) procedures. Particular attention has been paid to the parametrization of the dimethylamino group in ring A, for which several energy minima were found. The reliability of the force field has been checked comparing the results obtained from a classical molecular dynamics simulation with quantum mechanics ab initio energy calculations. The development of the topotecan force field makes it possible to carry out reliable simulations of the topotecan-topoisomerase-DNA ternary complex, thus allowing the investigation of important biological questions, such as the selective resistance to topotecan caused by single residue topoisomerase I mutations. © 2009 Springer-Verlag. Source


Chandramouli B.,University of Rome Tor Vergata | Chillemi G.,Interuniversities Consortium for Supercomputing Applications | Abbate I.,National Institute For Infectious Diseases L Spallanzani | Capobianchi M.R.,National Institute For Infectious Diseases L Spallanzani | And 3 more authors.
Journal of Biomolecular Structure and Dynamics | Year: 2012

The entry of HIV-1 into a host cell requires the interaction of envelope glycoprotein gp120 with CD4 receptor as well as a co-receptor, which can be either CCR5 or CXCR4. The third variable loop (V3) of HIV-1 gp120 plays an important role in co-receptor selection (CCR5 or CXCR4) and also acts as an epitope for neutralizing antibodies against gp120. Here we have performed long time molecular dynamics simulations of two gp120 structures that are representatives of a R5 and X4 strains in the CD4-free and CD4-bound states. The results indicate some conserved features in both systems, such as the rigidity of the gp120 core, the conservation of the CD4 Phe43-gp120 binding cavity contacts, a high flexibility of the V3 loop particularly in the CD4 bound form. Analysis of the distribution of V3 loop's net charge shows it to be more positive for the gp120 sequences selecting CXCR4 co-receptor, letting us to propose that V3 loop net charge and flexibility are the two main elements in the co-receptor selection. ©Adenine Press (2012). Source


Tesauro C.,University of Rome Tor Vergata | Fiorani P.,University of Rome Tor Vergata | D'annessa I.,Interuniversities Consortium for Supercomputing Applications | Chillemi G.,Interuniversities Consortium for Supercomputing Applications | And 2 more authors.
Biochemical Journal | Year: 2010

The interaction of human topoisomerase I and erybraedin C, a pterocarpan purified from the plant Bituminaria bituminosa, that was shown to have an antitumour activity, was investigated through enzymatic activity assays and molecular docking procedures. Erybraedin C is able to inhibit both the cleavage and the religation steps of the enzyme reaction. In both cases, preincubation of the drug with the enzyme is required to produce a complete inhibition. Molecular docking simulations indicate that, when interacting with the enzyme alone, the preferential drugbinding site is localized in proximity to the active Tyr723 residue, with one of the two prenilic groups close to the active-site residues Arg488 and His632, essential for the catalytic reaction. When interacting with the cleavable complex, erybraedin C interacts with both the enzyme and DNA in a way similar to that found for topotecan. This is the first example of a natural compound able to act on both the cleavage and religation reaction of human topoisomerase I. © The Authors Journal compilation © 2010 Biochemical Society. Source


Coletta A.,University of Rome Tor Vergata | Morozzo Della Rocca B.,University of Rome Tor Vergata | Jaisankar P.,Indian Institute of Science | Majumder H.K.,Indian Institute of Science | And 3 more authors.
Journal of Physical Chemistry A | Year: 2010

The geometrical optimization of (3,3′)-diindolylmethane (DIM), an inhibitor of the bisubunit enzyme topoisomerase I from Leishmania donovani, a pathogenic protozoan parasite, mostly diffused in developing countries, has been carried out through quantum mechanical calculation. Using first-principle DFT restrained geometrical optimization, a potential energy surface has been constructed to identify a set of local minimum energy conformations of DIM. Starting from these conformations, the experimental UV-vis absorption spectrum in aqueous solution has been reproduced through TD-DFT calculations. A molecular mechanics classical force-field has been also parametrized and tested, verifying the correct coherence between the canonical ensemble obtained from molecular dynamics simulation and the potential energy surface calculation. The force field has been used to elucidate the interaction of DIM with a 22 bp DNA double strand. The best docked DIM-DNA complexes display a binding energy pretty similar to the experimental energy and are all located in the DNA minor groove, strongly suggesting that DIM is a minor groove binder. © 2010 American Chemical Society. Source

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