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Biomedical subjects

F J Luque

Publications and source records attributed to F J Luque.

At least 37 records · Page 2Linked to original sources
PubMed1999

Fractional description of free energies of solvation.

A new and rigorous method for the fractional description of solvation and transfer free energies is presented. The method is based on the use of the Miertus-Scrocco-Tomasi self-consistent reaction field method (MST-SCRF), and allows for a rigorous partition of the total solvation free energy into surface elements. The method gives a complete picture of the hydrophobicity/hydrophilicity of molecules. Present results allow us to expect that the method might provide useful information in drug design and molecular modeling studies.

Benzene Derivatives↗
PubMed1999

Role of sugar re-puckering in the transition of A and B forms of DNA in solution. A molecular dynamics study.

State of the art molecular dynamic simulations show that simple modification of the sugar puckering of 2'deoxyriboses leads to a reversible change between two stable forms of DNA which resemble very closely the canonical A and B duplex forms. Analysis of the A-type and B-type structures reveals interesting, and previously unknown features of these two families of conformations of the DNA.

Carbohydrates↗
PubMed1998

Salt bridge interactions: stability of the ionic and neutral complexes in the gas phase, in solution, and in proteins.

A theoretical study on the stability of the salt bridges in the gas phase, in solution, and in the interior of proteins is presented. The study is mainly focused on the interaction between acetate and methylguanidinium ions, which were used as model compounds for the salt bridge between Asp (Glu) and Arg. Two different solvents (water and chloroform) were used to analyze the effect of varying the dielectric constant of the surrounding media on the salt bridge interaction. Calculations in protein environments were performed by using a set of selected protein crystal structures. In all cases attention was paid to the difference in stability between the ion pair and neutral hydrogen-bonded forms. Comparison of the results determined in the gas phase and in solution allows us to stress the large influence of the environment on the binding process, as well as on the relative stability between the ionic and neutral complexes. The high anisotropy of proteins and the local microenvironment in the interior of proteins make a decisive contribution in modulating the energetics of the salt bridge. In general, the formation of salt bridges in proteins is not particularly favored, with the ion pair structure being preferred over the interaction between neutral species.

Acetates↗
PubMed1998

On the potential role of the amino nitrogen atom as a hydrogen bond acceptor in macromolecules.

Crystallographic studies of duplex DNA have indicated that opposing exocyclic amino groups may form close NH⋯:N contacts. To study the nature of such interactions, we have examined the database of small molecule, high-resolution crystal structures for more accurate examples of this type of unconventional interaction. We have found cases where the amino groups in guanine and adenine bases accept hydrogen bonds from conventional donors, such as amino or hydroxyl groups. More frequently, the purine amino group was found to contact closely electropositive C-H groups. Searches of the nucleic acid structural databases also yielded several examples where the purine amino group is contacted by hydrogen bond donors in macromolecules. Ab initio calculations indicate that the hydrogen-amino contact is improved energetically when the amino group moves from the conventional geometry, where all atoms are co-planar with the base, to one in which the hydrogen atoms lie out of the plane and the nitrogen is at the apex of a pyramid, resulting in polarization of the amino group. The combined structural and theoretical data suggest that the amino group is flexible, and can accommodate close contacts, because the resulting polarization permits electropositive atoms to approach the amino group nitrogen more closely than expected for their conventional van der Waals radii. The flexibility of the amino group may permit particular DNA conformations that enforce hydrogen-amino contacts to optimize favorable stacking interactions, and it may play a role in the recognition of nucleosides. We speculate that the amino group can accept hydrogen bonds under special circumstances in macromolecules, and that this ability might play a mechanistic role in catalytic processes such as deamination or amino transfer.

Crystallography↗
PubMed1998

Is polarization important in cation-pi interactions?

The importance of cation->aromatic polarization effects on cation-pi interactions has been explored. Theoretical calculations demonstrate that polarization is a large contribution to cation-aromatic interactions, and particularly to cation-pi interactions. For a series of compounds with a similar aromatic core, polarization is constant and makes small influence in the relative cation-binding energies. However, when the aromatic core changes polarization contributions might be very different. We found that the generalized molecular interaction potential with polarization is a very fast and powerful tool for the prediction of cation binding of aromatic compounds.

Journal Article↗
PubMed1997

Role of tautomerism of 2-azaadenine and 2-azahypoxanthine in substrate recognition by xanthine oxidase.

The tautomerism of 2-azaadenine and 2-hypoxanthine has been examined in the gas phase and in aqueous solution. The tautomerism in the gas phase has been studied by means of semiempirical and ab initio quantum-mechanical computations, as well as density-functional calculations. The influence of the aqueous solvent on the relative stability between tautomers has been estimated from self-consistent reaction field calculations performed with different high-level continuum models. The results provide a detailed picture of the tautomeric preference for these purine bases. The importance of tautomerism in the substrate recognition by xanthine oxidase is discussed. Finally, the rate of oxidation of 2-azaadenine and 2-hypoxanthine by xanthine oxidase is discussed in terms of the recognition model at the enzyme active site.

Adenine↗
PubMed1997

Helical preferences of alanine, glycine, and aminoisobutyric homopeptides.

The stability between helical conformations of homopeptides of alanine, glycine, and aminoisobutyric acid has been studied by means of quantum-mechanical methods. The influence of peptide length on the relative stability between helical conformations has also been analyzed by means of systematic studies for peptides of size up to 11 residues. Finally, the influence of the solvent has been examined by using self-consistent reaction field methods. The results provide a detailed picture of the modulation exerted by these factors on the helical preferences of these peptides.

Alanine↗
PubMed1996

Tautomerism of xanthine and alloxanthine: a model for substrate recognition by xanthine oxidase.

Tautomerism of neutral xanthine and alloxanthine has been examined both in the gas phase and in aqueous solution. The tautomeric preference in the gas phase has been studied by means of semiempirical and ab initio quantum-mechanical computations with inclusion of correlation effects at the Møller-Plesset level, and from density-functional calculations. The influence of solvent on the relative stability between tautomers has been estimated from self-consistent reaction field calculations performed with different models. The results provide a detailed picture of tautomerism for these biologically relevant purine bases. The functional implications in the recognition by xanthine oxidase are analyzed from inspection of the interaction patterns of the most stable tautomeric forms. A model for the recognition of these purine derivatives in the enzyme binding site is discussed.

Binding Sites↗
PubMed1995

Molecular dynamics study of the binding of elsamicin A to DNA.

Molecular mechanics (MM) and dynamics (MD) were used to examine the conformational flexibility of elsamicin A, an antitumour antibiotic, in aqueous solution. Furthermore, MM and MD simulations were performed to obtain the first three-dimensional model of the elsamicin-A-DNA complex. Comparison of MD simulations of free and DNA-bound elsamicin A provided insight into the mechanism of DNA cleavage. Moreover, the drug-DNA complexes were analyzed to investigate specific drug-DNA interactions, as well as the role of the solvent water molecules in the drug-DNA binding. On the basis of the results derived from these simulations, several issues related to the sequence-selective binding of elsamicin A to DNA are discussed.

Aminoglycosides↗
PubMed1994

DNA sequence-specific reading by echinomycin: role of hydrogen bonding and stacking interactions.

The binding of echinomycin to DNA hexamers of the form GpApXpZpTpC, where the central XpZ step can be CpG, TpA, GpC, or ApT, has been studied by molecular modeling and molecular mechanics techniques. Interaction energies have also been calculated for the complexation of echinomycin with sequences containing the preferred central CpG step and different flanking base pairs. Besides, two more sets of sequences incorporating either 2,6-diaminopurine (DAP) or hypoxanthine in place of adenine or guanine, respectively, have been examined. The aim of this work was to evaluate the relative importance of hydrogen-bonding and stacking interactions in the association of echinomycin with DNA and further rationalize the experimental evidence. The results of these calculations are in consonance with available data from footprinting experiments and appear to support our previous hypothesis that, in addition to the crucial intermolecular hydrogen bonds in the central region, the stacking interactions involving the quinoxaline-2-carboxamide chromophores of the drug and the DNA base pairs play an important role in modulating the binding specificity of this bisintercalating antitumor antibiotic. This is most clearly seen when sequences with similar minor-groove environments are compared (e.g. CpI vs TpA or CpG vs TpDAP). The dipole moment of N-methylquinoxaline-2-carboxamide has been measured (mu = 4.15 +/- 0.03 D) and compares very well with the calculated value (mu = 4.14 D). The fact that G:C, I:C, A:T, and DAP:T base pairs are shown to be endowed with distinct van der Waals and electrostatic stacking properties with respect to this heteroaromatic ring system could have important implications for the design of novel DNA mono- and bis-intercalating agents.

2-Aminopurine↗
PubMed1994

Binding of echinomycin to d(GCGC)2 and d(CCGG)2: distinct stacking interactions dictate the sequence-dependent formation of Hoogsteen base pairs.

Molecular dynamics simulations have been used to explore the behavior of the complexes of echinomycin with the DNA tetramers d(GCGC)2 and d(CCGG)2 in which the terminal bases have been paired according to either a Hoogsteen or a Watson-Crick hydrogen bonding scheme. The energy of the four resulting complexes has been monitored along the dynamics trajectories and the interaction energy between echinomycin and DNA has been decomposed into contributions arising from the planar aromatic systems and the depsipeptide part of the antibiotic. Our calculations predict a large increase in overall stabilization upon protonation of the terminal cytosines and subsequent Hoogsteen pair formation in the complex of echinomycin with d(GCGC)2 but not with d(CCGG)2, in agreement with the experimental evidence [Gao and Patel, Quart. Rev. Biophys. 22, 93-138 (1989)]. The conformational preferences appear to arise mainly from differential stacking interactions in which the electrostatic component is shown to play a dominant role. Differences in hydrogen bonding patterns are also found among the complexes and these are compared in relation to available crystal structures. The binding of echinomycin to DNA appears as a complex process involving many interrelated variables.

Base Composition↗
PubMed1990

A practical procedure for the determination of electrostatic charges of large molecules.

A practical procedure for the precise determination of electrostatic charges, which are evaluated by fitting the rigorous quantum mechanical molecular electrostatic potential to a monopole-monopole expression, is presented. The proposal of this procedure arises from the study of the minimum requirements necessary to obtain reliable electrostatic charges. Such a study is focused on: (i) the dependence of the electrostatic charges on the set of points where the quantum mechanical and the monopole-monopole molecular electrostatic potentials are fitted; thus, both the influence of the number of points and their distribution in layers located out of the van der Waals radii of the atoms are examined, and (ii) the reliability of the use of fractional models for the evaluation of electrostatic charges of large molecules. Results point out that the optimum number of points is defined by a density of points ranging from 0.45 to 0.60 points/A2 when four layers (separated by 0.2 A) are considered. Nevertheless, the use of only two layers (separated by 0.4 A) for large molecules is recommended, thus enabling one to obtain reliable charges at a reduced computational cost. Moreover, results justify the use of fractional models for the determination of electrostatic charges of extremely large molecules, even when aromatic structures exist.

Adenosine↗
PubMed1988

POEMS: program for outliers elimination in multidimensional space.

A Program for Outliers Elimination in Multidimensional Space (POEMS), which allows the user to eliminate outliers from training spaces as a prior step to any statistical study, is presented. Even though the program can be applied to any scientific field, the characteristics of POEMS makes it particularly suitable for 'series design' on Quantitative Structure-Activity Relationships studies.

Algorithms↗