RESUMEN
The alpha-aminoisobutyric acid-D-proline (Aib-(D)Pro) dipeptide is an obligatory Type I' beta-turn forming segment that nucleates hairpin formation.
Asunto(s)
Dipéptidos/química , Secuencia de Aminoácidos , Enlace de Hidrógeno , Modelos Moleculares , Estructura Secundaria de ProteínaRESUMEN
A comprehensive statistical analysis of the geometric parameters of peptide chains in a reduced dataset of protein-peptide complexes in Protein Data Bank (PDB) is presented. The angular variables describing the backbone conformations of amino acid residues in peptide chains shed insights into the conformational preferences of peptide residues interacting with protein partners. Nonparametric statistical approaches are employed to evaluate the interrelationships and associations in structural variables. Grouping of residues based on their structure into chemical classes reveals characteristic trends in parameter relationships. A comparison of canonical amino acid residues in free peptide structures in Cambridge structural database (CSD) with identical residues in PDB complexes, suggests that the information can be integrated from both the structural repositories enabling efficient and accurate modeling of biologically active peptides.
Asunto(s)
Bases de Datos de Proteínas , Péptidos/química , Proteínas/química , Amidas/química , Aminoácidos/análisis , Aminoácidos/química , Interpretación Estadística de Datos , Modelos Moleculares , Péptidos/metabolismo , Conformación Proteica , Proteínas/metabolismo , Azufre/químicaRESUMEN
The first computational study of the folding and dynamics of a hydrophobic ß-hairpin containing a central heterochiral diproline segment is reported. Linear hydrophobic sequences containing centrally positioned diproline motifs, heterochiral (DL/LD) and homochiral (LL/DD)), are investigated for their ability to form ß-hairpins. Heterochiral diproline motifs (LD/DL) reveal the formation of stable ß-hairpins with the backbone adopting ß-turn conformation and the formation of backbone hydrogen bonds with antiparallel cross-strand registry, whereas the homochiral diproline (LL/DD) containing sequences tend to adopt PPII helix conformation. The competition between the ß-turn formation and the backbone H-bond ladder of the antiparallel ß-strands in heterochiral diproline containing sequences is employed to validate the hypothesis that ß-turn formation precedes inter-strand registry in the folding of a ß-hairpin ("zipper" mechanism). The observation of noncanonical hydrogen bonds leads to a folded ß-hairpin-like conformation and points to the existence of relatively stable transition state intermediates, between the unfolded (extended) and folded (ß-hairpin) states. The MD simulations are in excellent agreement with the experimental studies on the model system and constitute the very first computational investigation of the folding and dynamics of a completely hydrophobic synthetic ß-hairpin containing heterogeneous residues of mixed chirality.
Asunto(s)
Simulación de Dinámica Molecular , Pliegue de Proteína , Estructura Secundaria de Proteína , Proteínas/química , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Modelos MolecularesRESUMEN
The protein sequence space is vast and diverse, spanning across different families. Biologically meaningful relationships exist between proteins at superfamily level. However, it is highly challenging to establish convincing relationships at the superfamily level by means of simple sequence searches. It is necessary to design a rigorous sequence search strategy to establish remote homology relationships and achieve high coverage. We have used iterative profile-based methods, along with constraints of sequence motifs, to specify search directions. We address the importance of multiple start points (queries) to achieve high coverage at protein superfamily level. We have devised strategies to employ a structural regime to search sequence space with good specificity and sensitivity. We employ two well-known sequence search methods, PSI-BLAST and PHI-BLAST, with multiple queries and multiple patterns to enhance homologue identification at the structural superfamily level. The study suggests that multiple queries improve sensitivity, while a pattern-constrained iterative sequence search becomes stringent at the initial stages, thereby driving the search in a specific direction and also achieves high coverage. This data mining approach has been applied to the entire structural superfamily database.
RESUMEN
A one-dimensional water wire has been characterized by X-ray diffraction in single crystals of the tripeptide Ac-Phe-Pro-Trp-OMe. Crystals in the hexagonal space group P6(5) reveal a central hydrophobic channel lined by aromatic residues which entraps an approximately linear array of hydrogen bonded water molecules. The absence of any significant van der Waals contact with the channel walls suggests that the dominant interaction between the "water wire" and "peptide nanotube" is electrostatic in origin. An energy difference of 16 kJ mol(-1) is estimated for the distinct orientations of the water wire dipole with respect to the macrodipole of the peptide nanotube. The structural model suggests that Grotthuss type proton conduction may, through constricted hydrophobic channels, be facilitated by concerted, rotational reorientation of water molecules.
Asunto(s)
Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Oligopéptidos/química , Agua/química , Cristalografía por Rayos X , Conformación Proteica , Protones , Electricidad EstáticaRESUMEN
The pseudoproline residue (Psi Pro, L-2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid) has been introduced into heterochiral diproline segments that have been previously shown to facilitate the formation of beta-hairpins, containing central two and three residue turns. NMR studies of the octapeptide Boc-Leu-Phe-Val-(D)Pro-Psi Pro-Leu-Phe-Val-OMe (1), Boc-Leu-Val-Val-(D)Pro-Psi Pro-Leu-Val-Val-OMe (2), and the nonapeptide sequence Boc-Leu-Phe-Val-(D)Pro-Psi Pro-(D)Ala-Leu-Phe-Val-OMe (3) established well-registered beta-hairpin structures in chloroform solution, with the almost exclusive population of the trans conformation for the peptide bond preceding the Psi Pro residue. The beta-hairpin conformation of 1 is confirmed by single crystal X-ray diffraction. Truncation of the strand length in Boc-Val-(D)Pro-Psi Pro-Leu-OMe (4) results in an increase in the population of the cis conformer, with a cis/trans ratio of 3.65. Replacement of Psi Pro in 4 by (L)Pro in 5, results in almost exclusive population of the trans form, resulting in an incipient beta-hairpin conformation, stabilized by two intramolecular hydrogen bonds. Further truncation of the sequence gives an appreciable rise in the population of cis conformers in the tripeptide Piv-(D)Pro-Psi Pro-Leu-OMe (6). In the homochiral segment Piv-Pro-Psi Pro-Leu-OMe (7) only the cis form is observed with the NMR evidence strongly supporting a type VIa beta-turn conformation, stabilized by a 4-->1 hydrogen bond between the Piv (CO) and Leu (3) NH groups. The crystal structure of the analog peptide 7a (Piv-Pro-Psi(H,CH3)Pro-Leu-NHMe) confirms the cis peptide bond geometry for the Pro-Psi(H,CH3)Pro peptide bond, resulting in a type VIa beta-turn conformation.