RESUMEN
A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.
Asunto(s)
ADN/química , Biología Molecular/tendencias , Ácidos Nucleicos/química , Oligonucleótidos/síntesis química , Catálisis , Codón , Estructura Molecular , Ácidos Nucleicos/síntesis química , Oligonucleótidos/química , Fosfatos/química , Sulfonas/químicaRESUMEN
A bona fide consensus prediction for the secondary and supersecondary structure of the serine-threonine specific protein phosphatases is presented. The prediction includes assignments of active site segments, an internal helix, and a region of possible 3(10) helical structure. An experimental structure for a member of this family of proteins should appear shortly, allowing this prediction to be evaluated.
Asunto(s)
Modelos Estructurales , Fosfoproteínas Fosfatasas/química , Estructura Secundaria de Proteína , Secuencia de Aminoácidos , Sitios de Unión , Datos de Secuencia Molecular , Conformación ProteicaRESUMEN
A consensus prediction for the secondary structure of the pleckstrin homology (PH) domain is presented. The prediction is based on an analysis of patterns of conservation and variation of homologous protein sequences. The structure is predicted to be formed largely from beta strands with a single alpha helix.
Asunto(s)
Proteínas Sanguíneas/química , Fosfoproteínas , Estructura Secundaria de Proteína , Secuencia de Aminoácidos , Simulación por Computador , Secuencia Conservada , Variación Genética , Modelos Moleculares , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
To learn how secondary structure assignments diverge during divergent evolution, pairs of proteins with solved crystal structures were aligned and their assignments compared as a function of evolutionary distance. Residues assigned in one structure to a helix or a strand are frequently paired with residues assigned in the other to a coil. However, residues assigned to a helix in one structure are almost never paired with residues assigned to a strand in the other. This suggests additional limitations to the "three state residue-by-residue" score commonly used to evaluate secondary structure predictions and suggests recommendations for how secondary structure predictions should be scored to assess accurately their value as starting points for modelling tertiary structure.
Asunto(s)
Evolución Biológica , Estructura Secundaria de Proteína , Cristalografía por Rayos X , Estructura Terciaria de Proteína , Proteínas/química , Proteínas/genéticaRESUMEN
A new paradigm for predicting the secondary and tertiary structure of functional proteins from sequence data has emerged from detailed models of how natural selection, conservation, and neutral drift, the three fundamental factors in molecular evolution, leave their mark upon protein sequences. Structural information is extracted from a set of aligned homologous sequences via an analysis of patterns of conservation and variation between proteins with quantitatively defined evolutionary relationships. Tertiary structural information is obtained prior to the assignment of secondary structure, where it plays an important role. Throughout, structural predictions are made with the active involvement of a biochemist whose expertise and insight is critical both for making the prediction and in analyzing its successful and unsuccessful parts. Secondary structure predictions are evaluated based on their ability to sustain an effort to model tertiary structure. Several predictions made using the new paradigm can now be compared with those made under the classical paradigm, including a neural network. The results obtained from the new paradigm are clearly superior to those obtained with the classical paradigm, at least within the protein families that were examined.
Asunto(s)
Modelos Químicos , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Secuencia de Aminoácidos , Bioquímica/tendencias , Evolución Biológica , Datos de Secuencia Molecular , Proteínas/genética , Alineación de Secuencia/métodos , Homología de Secuencia de AminoácidoRESUMEN
A secondary structure has been predicted for the hemorrhagic metalloproteases using a method developed in Zurich that extracts structural information from patterns of conservation and variation in homologous protein sequences. This prediction tests the limits of the method when applied to a small number of homologous sequences that have undergone only modest evolutionary divergence. Predictions were also obtained using a neural network developed by Sander and coworkers, to date the best fully automated method for predicting secondary structure, and using the classical Chou-Fasman and GOR heuristics. The predictions are different. No crystal structure is known within this protein family, but one is expected shortly. Therefore, this prediction should contribute significantly to the evaluation of the relative merits of these prediction methods.
Asunto(s)
Metaloendopeptidasas/química , Estructura Secundaria de Proteína , Venenos de Serpiente/toxicidad , Secuencia de Aminoácidos , Animales , Hemorragia , Metaloendopeptidasas/toxicidad , Datos de Secuencia MolecularRESUMEN
Surface residues, interior residues, and parsing residues, together with a secondary structure derived from these, are predicted for the MoFe nitrogenase protein in advance of a crystal structure of the protein, scheduled shortly to appear in Nature. By publishing this prediction, we test our method for predicting the conformation of proteins from patterns in the divergent evolution of homologous protein sequences in a way that places the method 'at risk'.
