Biomedical subjects

X de la Cruz

Publications and source records attributed to X de la Cruz.

6 recordsLinked to original sources

PubMed2004

Sequence-based prediction of pathological mutations.

The development of methods to assess the impact of amino acid mutations on human health has become an important goal in biomedical research, due to the growing number of nonsynonymous SNPs identified. Within this context, computational methods constitute a valuable tool, because they can easily process large amounts of mutations and give useful, almost cost-free, information on their pathological character. In this paper we present a computational approach to the prediction of disease-associated amino acid mutations, using only sequence-based information (amino acid properties, evolutionary information, secondary structure and accessibility predictions, and database annotations) and neural networks, as a model building tool. Mutations are predicted to be either pathological or neutral. Our results show that the method has a good overall success rate, 83%, that can reach 95% when trained for specific proteins. The methodology is fast and flexible enough to provide good estimates of the pathological character of large sets of nonsynonymous SNPs, but can also be easily adapted to give more precise predictions for proteins of special biomedical interest.

Databases, Protein↗

PubMed1999

Factors limiting the performance of prediction-based fold recognition methods.

In the past few years, a new generation of fold recognition methods has been developed, in which the classical sequence information is combined with information obtained from secondary structure and, sometimes, accessibility predictions. The results are promising, indicating that this approach may compete with potential-based methods (Rost B et al., 1997, J Mol Biol 270:471-480). Here we present a systematic study of the different factors contributing to the performance of these methods, in particular when applied to the problem of fold recognition of remote homologues. Our results indicate that secondary structure and accessibility prediction methods have reached an accuracy level where they are not the major factor limiting the accuracy of fold recognition. The pattern degeneracy problem is confirmed as the major source of error of these methods. On the basis of these results, we study three different options to overcome these limitations: normalization schemes, mapping of the coil state into the different zones of the Ramachandran plot, and post-threading graphical analysis.

Algorithms↗

PubMed1996

A 15 amino acid stretch close to the Grb2-binding domain defines two differentially expressed hSos1 isoforms with markedly different Grb2 binding affinity and biological activity.

We compared structure, expression and functional properties of two hSos1 cDNA isoforms (IsfI and Isf II) isolated, respectively, from human fetal brain and adult skeletal muscle libraries. IsfI and IsfII nucleotide sequences differ only by the presence in IsfII of an inframe 45 hp insertion located near the first proline-rich motif required for Grb2 binding. Some human tissues express only one isoform whereas others express different proportions of both in fetal and adult stages. In vitro binding assays and in vivo functional studies showed that MI exhibits significantly higher Grb2 binding affinity and biological activity than IsfI. These results suggest that functionally different hSos1 isoforms, with differential tissue expression and distribution, play important regulatory roles in the mechanisms controlling Ras activation in different tissues and/or developmental stages.

Adaptor Proteins, Signal Transducing↗

PubMed1996

The structural homology between uteroglobin and the pore-forming domain of colicin A suggests a possible mechanism of action for uteroglobin.

Although the exact physiological function of uteroglobin is not known, it has been suggested that it may function by inhibiting phospholipase A2. We have found that the uteroglobin fold is embedded in that of the poreforming domain of colicin A. Colicin A is an antibiotic protein that kills sensitive Escherichia coli cells by forming a pore in their phospholipid membrane. The RMS deviation between the C alpha atoms after the structural alignment is 2.39 A for the 52 superimposed residues. In the alignment, uteroglobin helices 1, 2, 3, and 4 align with colicin A helices 6, 7, 3, and 4, respectively. The motif is strongly amphipathic in both proteins. On the basis of this common structural motif and of known experimental data on both proteins, we propose that UG binds to the membrane surface by lying on it monotopically. The phospholipase A2 inhibition would follow this initial binding step.

Animals↗

PubMed1994

Investigation of shape variations in the antibody binding site by molecular dynamics computer simulation.

Molecular dynamics simulations have been used to investigate the flexibility and variations in the shape of the binding site of an antibody against human Rhinovirus serotype 2 (HRV2) and its complex with a 15 amino acid oligopeptide, the structure of which has been recently determined by X-ray crystallography. During the simulation of the unbound antibody the binding site, defined in terms of the hypervariable regions or complementarity determining regions (CDRs), shows significant fluctuations in shape. For the complex such variations in the shape of the binding site were reduced. The largest fluctuations in the unbound antibody occurred within the CDR-H3. The largest differences between the bound and unbound crystal structures are also associated with CDR-H3. The relative displacements of the loops have been analysed in terms of internal distortions, rigid body motions of the loops and changes with respect to the framework regions. The degree to which the motions of the loops are correlated and the variation in the volume of the binding pocket during the simulation have also been examined.

Amino Acid Sequence↗

PubMed1992

Representation of noncovalent interactions in protein structures.

The energetics of solvent-atom and atom-atom nonbonded interactions can be described, for protein structures, in terms of the accessible and the contact atomic surface areas, respectively. This type of description emphasizes the importance of the local environment around groups in the three-dimensional structure of protein molecules. The graphical representation of nonbonded interactions according to this description allows one to visualize the spatial extent and distribution of these interactions and the relative stability of atoms or atomic groups in known or modified protein conformations. Applications of this short range description and of its graphical representation will be discussed.

Computer Graphics↗