The solution structures of d(GAAAACGTTTTC) 2 and of its methylated derivative d(GAAAAMe 5 CGTTTTC) 2 have been determined by NMR and molecular modelling in order to examine the impact of cytosine methylation on the central CpG conformation. Detailed 1 H NMR and 31 P NMR investigation of the two oligomers includes quantitative NOESY, 2D homonuclear Hartmann±Hahn spectroscopy, double-quantum-filtered COSY and heteronuclear 1 H-31 P correlation. Back-calculations of NOESY spectra and simulations of double-quantumfiltered COSY patterns were performed to gain accurate information on interproton distances and sugar phase angles. Molecular models under experimental constraints were generated by energy minimization by means of the molecular mechanics program jumna. The morass software was used to iteratively refine the structures obtained. After methylation, the oligomer still has a B-DNA conformation. However, there are differences in the structural parameters and the thermal stability as compared to the unmethylated molecule. Careful structural analysis shows that after methylation CpG departs from the usual conformation observed in other ACGT tetramers with different surroundings. Subtle displacements of bases, sugars and backbone imposed by the steric interaction of the two methyl groups inside the major groove are accompanied by severe pinching of the minor groove at the C-G residues.Keywords: DNA; 2D NMR; modelling; cytosine methylation; CpG; adenine tract.DNA methylation at cytosines in CpG steps is recognized as an important event in biological processes that control gene expression. Methylation turns off the transcription of genes involved in mammal development [1] and genomic imprinting [2], and abolishes the immune response induced by oligonucleotide motifs containing a CpG step flanked by two purines and two pyrimidines in the 5 H and 3 H directions, respectively [3]. The hypothesis that gene silencing stems from blocking the binding of transcription factors at methylated CpG has led to several investigations designed to unveil possible structural singularities of the methylated sequence as compared to the unmodified one. Crystallographic data show that cytosine methylation in the CMe 5 CTG oligomer only induces a slight structural alteration [4]. NMR analysis has underlined the marked conformational difference between the octamers d(CATCGATG) 2 and d(CTTCGAAG) 2 , despite the same central four-base sequence, and their specific structural response to the methylation of the central cytosine [5]. The 1 H NMR results show that cytosine methylation induces more significant structural effects in the first oligomer than in the other. The conclusions reached by 1 H NMR have been corroborated by 1 H-31 P coupling constant and 31 P chemical shift investigation. These studies have shown that the CpG backbone is more sensitive to methylation in d(CATCGATG) 2 than in the second octamer. The observation that the conformation of the central tetranucleotide is strongly affected by its 5 H and 3 H environment is in line wit...

Comparative molecular field analysis (CoM-FA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoM-SIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

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Nuclear Magnetic Resonance (NMR), Surface‐Enhanced Resonance Raman Scattering (SERRS), and Density Functional Theory (DFT) were used to study 8‐substituted acetylene‐ and thienylacetylene‐diphenylnaphthopyran photochromic compounds. The purpose of this work is to determine the effect of the 8‐acetylene substituent on the photochromic equilibrium. NMR spectroscopy shows that photocoloration by UV irradiation at low temperature leads to a mixture of transoid isomers (TC and TT) and a small amount of an allenyl‐naphthol structure. The mixture is further enriched in this latter isomer by subsequent visible irradiation. Some photoproducts are identified by analysis of the changes in the SERRS spectra of an irradiated solution with time. To assist spectral assignment, the vibrational frequencies of compounds (1) and (2) and their photoproducts were computed at optimized geometries and compared with the observed Raman bands. Copyright © 2007 John Wiley & Sons, Ltd.

Verbascoside and rutin possess anti-cancer properties and are capable of repairing DNA damaged by oxygen radicals, acting as powerful antioxidants. Based on kinetic measurements and experiments on tumor cells, docking studies of the two ligand molecules with the receptor telomeric DNA fragments have been carried out. The docking calculations performed using JUMNA software showed that the both molecules can be docked into the minor groove of telomeric DNA and form complexes with suitable geometry for electron transfer between guanine radical and ligands. The reaction mechanism via the electron transfer process is further confirmed through energy calculations for transition states using MOPAC 93 program. Complexes can be formed without major distortion of DNA structure and are further stabilized by the interaction of DNA with the saccharide side-groups. By comparing their energies, the difference of activities of the two compounds can be explained.

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A theoretical investigation of SBH and a bicomplex ion, [(Fe 111 (SBH)2)]' is used as a basis to control and clarifjr previous vibrational assignments for complexes formed between iron and ligands related to SBH.Main conclusions are the following : 1 . Complexation shifts the vC=O vibration by about 100 cm" towards low wavenumbers. vC=N and GHC=N modes are enhanced by complexation.3. In the complex, the enhanced vC=N mode hides the amide I1 vibration. 505

HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules.