RESUMO
Replacement of the main chain peptide bond by imidazole ring seems to be a promising tool for the peptide-based drug design, due to the specific prototropic tautomeric as well as amphoteric properties. In this study, we present that both tautomer and pH change can cause a conformational switch of the studied residues of alanine (1-4) and dehydroalanine (5-8) with the C-terminal peptide group replaced by imidazole. The DFT methods are applied and an environment of increasing polarity is simulated. The conformational maps (Ramachandram diagrams) are presented and the stability of possible conformations is discussed. The neutral forms, tautomers τ (1) and π (2), adapt the conformations αRτ (φ, ψ = - 75°, - 114°) and C7eq (φ, ψ = - 75°, 66°), respectively. Their torsion angles ψ differ by about 180°, which results in a considerable impact on the peptide chain conformation. The cation form (3) adapts both these conformations, whereas the anion analogue (4) prefers the conformations C5 (φ, ψ = - 165°, - 178°) and ß2 (φ, ψ ~ - 165°, - 3°). Dehydroamino acid analogues, the tautomers τ (5) and π (6) as well as the anion form (8), have a strong tendency toward the conformations ß2 (φ, ψ = - 179°, 0°) and C5 (φ, ψ = - 180°, 180°). The preferences of the protonated imidazolium form (7) depend on the environment. The imidazole ring, acting as a donor or acceptor of the hydrogen bonds created within the studied residues, has a profound effect on the type of conformation.
Assuntos
Aminoácidos , Peptídeos , Aminoácidos/química , Isomerismo , Peptídeos/química , Imidazóis , Concentração de Íons de Hidrogênio , Conformação ProteicaRESUMO
Post-translational modified thiazole-amino acid (Xaa-Tzl) residues have been found in macrocyclic peptides (e.g., thiopeptides and cyanobactins), which mostly inhibit protein synthesis in Gram + bacteria. Conformational study of the series of model compounds containing this structural motif with alanine, dehydroalanine, dehydrobutyrine and dehydrophenylalanine were performed using DFT method in various environments. The solid-state crystal structure conformations of thiazole-amino acid residues retrieved from the Cambridge Structural Database were also analysed. The studied structural units tend to adopt the unique semi-extended ß2 conformation; which is stabilised mainly by N-Hâ¯NTzl hydrogen bond, and for dehydroamino acids also by π-electron conjugation. The conformational preferences of amino acids with a thiazole ring were compared with oxazole analogues and the role of the sulfur atom in stabilising the conformations of studied peptides was discussed.
Assuntos
Aminoácidos/química , Tiazóis/química , Ligação de Hidrogênio , Conformação Molecular , Peptídeos/síntese química , Peptídeos/químicaRESUMO
Protein complexes with short linear motifs (SLiMs) are known to play important regulatory functions in eukaryotes. In this investigation, I have studied the structures deposited in PDB with SLiMs. The structures were grouped into three broad categories of protein-protein, protein-peptide, and the rest as others. Protein-peptide complexes were found to be most highly represented. The interfaces were evaluated for geometric features and conformational variables. It was observed that protein-protein and protein-peptide complexes show characteristic differences in residue pairings, which were quantified by evaluating normalized contact residue pairing frequencies. Interface residues adopt characteristic canonical residue conformations in the Ramachandran space, with a pronounced preference for positive Ï conformations. It was observed that phosphorylated residues have an unusual propensity to adopt the positive Ï conformations at the interface.
Assuntos
Peptídeos , Proteínas , Motivos de Aminoácidos , Bases de Dados de Proteínas , Conformação Molecular , Conformação Proteica , Proteínas/genéticaRESUMO
The Ramachandran map clearly delineates the regions of accessible conformational (φ-ψ) space for amino acid residues in proteins. Experimental distributions of φ, ψ values in high-resolution protein structures, reveal sparsely populated zones within fully allowed regions and distinct clusters in apparently disallowed regions. Conformational space has been divided into 14 distinct bins. Residues adopting these relatively rare conformations are presented and amino acid propensities for these regions are estimated. Inspection of specific examples in a completely "arid", fully allowed region in the top left quadrant establishes that side-chain and backbone interactions may provide the energetic compensation necessary for populating this region of φ-ψ space. Asn, Asp, and His residues showed the highest propensities in this region. The two distinct clusters in the bottom right quadrant which are formally disallowed on strict steric considerations correspond to the gamma turn (C7 axial) conformation (Bin 12) and the i + 1 position of Type II' ß turns (Bin 13). Of the 516 non-Gly residues in Bin 13, 384 occupied the i + 1 position of Type II' ß turns. Further examination of these turn segments revealed a high propensity to occur at the N-terminus of helices and as a tight turn in ß hairpins. The ß strand-helix motif with the Type II' ß turn as a connecting element was also found in as many as 57 examples.
Assuntos
Aminoácidos/química , Estrutura Molecular , Conformação Proteica , Proteínas/química , Modelos MolecularesRESUMO
The conformational analysis of N-formyl-D-serine-D-alanine-NH2 dipeptide was studied using density functional theory methods at B3LYP, B3LYPâD3, and M06â2X levels using 6â311 + G (d,p) basis set in the gas and water phases. 87 conformers of 243 stable ones were located and the rest of them were migrated to the more stable geometries. Migration pattern suggests the more stable dipeptide model bears serine in ßL, γD, γL and the alanine in γL and γD configurations. The investigation of sideâchainâbackbone interactions revealed that the most stable conformer, γD-γL, is in the ßâturn region of Ramachandran map; therefore, serine-alanine dipeptide model should be adopted with a ßâturn conformation. Intramolecular hydrogen bonding in ßâturns consideration by QTAIM disclosed γD-γL includes three hydrogen bonds. The computed UVâVis spectrum alongside of NBO calculation showed the five main electronic transition bands derived of n â n* of intraâligand alanine moiety of dipeptide structure.
RESUMO
Proteins undergo motions in a range of amplitudes, from domain motions to backbone rotations, leading to changes in (φ,ψ) torsion angles and small-scale bond vibrations and angle bending. Here, we study the extent of variations in (φ,ψ) values in proteins and the effects of bond geometry variations due to vibrational motions in a protein on the accessible, (steric clash-free) (φ,ψ) space. We perform 1-fs timestep unconstrained molecular dynamics simulations on super-high-resolution protein structures. Extent of variations in bond geometry during the simulation is within acceptable ranges of bond lengths and angles. However, the steric clash-free (φ,ψ) space continuously changes as seen in bond geometry-specific (φ,ψ) steric maps at the residue level during simulations. (φ,ψ) regions that have steric clash at one timepoint can become steric clash-free at a different timepoint through minor adjustments to backbone bond lengths and angles. Also instances of (φ,ψ) transitions from the left to right half of the (φ,ψ) map in consecutive snapshots of the trajectory are seen. Although the two quadrants are separated by a steric clash-prone region, corresponding to a high-energy barrier, height of this barrier is lowered by adjusting the bond geometry such that a bridging region of steric clash-free, low-energy (φ,ψ) values is formed. We demonstrate the idea of dynamically varying nature of acceptable and accessible (φ,ψ) steric space in proteins, which has implications for protein folding; proteins could sample (φ,ψ) space which is originally considered to be inaccessible, during folding, through minor adjustments to their backbone bond geometry.
RESUMO
We report molecular dynamics simulations of three possible adducts of Fe(II) to the N-terminal 1-16 fragments of the amyloid-ß peptide, along with analogous simulations of Cu(II) and Zn(II) adducts. We find that multiple simulations from different starting points reach pseudo-equilibration within 100-300 ns, leading to over 900 ns of equilibrated trajectory data for each system. The specifics of the coordination modes for Fe(II) have only a weak effect on peptide secondary and tertiary structures, and we therefore compare one of these with analogous models of Cu(II) and Zn(II) complexes. All share broadly similar structural features, with mixture of coil, turn and bend in the N-terminal region and helical structure for residues 11-16. Within this overall pattern, subtle effects due to changes in metal are evident: Fe(II) complexes are more compact and are more likely to occupy bridge and ribbon regions of Ramachandran maps, while Cu(II) coordination leads to greater occupancy of the poly-proline region. Analysis of representative clusters in terms of molecular mechanics energy and atoms-in-molecules properties indicates similarity of four-coordinate Cu and Zn complexes, compared to five-coordinate Fe complex that exhibits lower stability and weaker metal-ligand bonding. Communicated by Ramaswamy H. Sarma.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Metais/metabolismo , Simulação de Dinâmica Molecular , Elementos de Transição/metabolismo , Análise por Conglomerados , Ligação de Hidrogênio , Ligação Proteica , Estrutura Secundária de ProteínaRESUMO
Ramachandran validation of protein structures is commonly performed using developments, such as MolProbity. We suggest tailoring such analyses by position-wise, geometry-specific steric-maps, which show (φ,ψ) regions with steric-clash at every residue position. These maps are different from the classical steric-map because they are highly sensitive to bond length and angle values that are used, in our steric-maps, as observed in the residue positions in super-high-resolution peptide and protein structures. (φ,ψ) outliers observed in such structures seldom have steric-clash. Therefore, we propose that a (φ,ψ) outlier is unacceptable if it is located within the steric-clash region of a bond geometry-specific steric-map for a residue position. These steric-maps also suggest position-specific accessible (φ,ψ) space. The PARAMA web resource performs in-depth position-wise analysis of protein structures using bond geometry-specific steric-maps.
Assuntos
Algoritmos , Peptídeos/química , Proteínas/química , Sequência de Aminoácidos , Mapeamento de Peptídeos , Conformação Proteica , Software , TermodinâmicaRESUMO
Using fine-tuned hydrogen bonding criteria, a library of coiled peptide fragments has been generated from a large set of high-resolution protein X-ray structures. This library is shown to be an improved representation of Ï/ψ torsion angles seen in intrinsically disordered proteins (IDPs). The Ï/ψ torsion angle distribution of the library, on average, provides good agreement with experimentally observed chemical shifts and 3 JHN-Hα coupling constants for a set of five disordered proteins. Inspection of the coil library confirms that nearest-neighbor effects significantly impact the Ï/ψ distribution of residues in the coil state. Importantly, 3 JHN-Hα coupling constants derived from the nearest-neighbor modulated backbone Ï distribution in the coil library show improved agreement to experimental values, thereby providing a better way to predict 3 JHN-Hα coupling constants for IDPs, and for identifying locations that deviate from fully random behavior.
Assuntos
Proteínas Intrinsicamente Desordenadas/química , Ressonância Magnética Nuclear Biomolecular , Biblioteca de Peptídeos , Proteínas Intrinsicamente Desordenadas/genética , Estrutura Secundária de ProteínaRESUMO
A protein can interact with DNA or RNA molecules to perform various cellular processes. Identifying or analyzing DNA/RNA binding site amino acid residues is important to understand molecular recognition process. It is quite possible to accurately model DNA/RNA binding amino acid residues in experimental protein-DNA/RNA complex by using the electron density map whereas, locating/modeling the binding site amino acid residues in the predicted three dimensional structures of DNA/RNA binding proteins is still a difficult task. Considering the above facts, in the present work, we have carried out a comprehensive analysis of dihedral angle preferences of DNA and RNA binding site amino acid residues by using a classical Ramachandran map. We have computed backbone dihedral angles of non-DNA/RNA binding residues and used as control dataset to make a comparative study. The dihedral angle preference of DNA and RNA binding site residues of twenty amino acid type is presented. Our analysis clearly revealed that the dihedral angles (φ, ψ) of DNA/RNA binding amino acid residues prefer to occupy (-89° to -60°, -59° to -30°) bins. The results presented in this paper will help to model/locate DNA/RNA binding amino acid residues with better accuracy.
Assuntos
Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Sítios de Ligação , DNA/química , RNA/química , Especificidade por SubstratoRESUMO
For the past 50 years, the Ramachandran map has been used effectively to study the protein structure and folding. However, though extensive analysis has been done on dihedral angle preferences of residues in globular proteins, related studies and reports of membrane proteins are limited. It is of interest to explore the conformational preferences of residues in transmembrane regions of membrane proteins which are involved in several important and diverse biological processes. Hence, in the present work, a systematic comparative computational analysis has been made on dihedral angle preferences of alanine and glycine in alpha and beta transmembrane regions (the two major classes of transmembrane proteins) with the aid of the Ramachandran map. Further, the conformational preferences of residues in transmembrane regions were compared with the non-transmembrane regions. We have extracted cation-pi interacting residues present in transmembrane regions and explored the dihedral angle preferences. From our observations, we reveal the higher percentage of occurrences of glycine in alpha and beta transmembrane regions than other hydrophobic residues. Further, we noted a clear shift in ψ-angle preferences of glycine residues from negative bins in alpha transmembrane regions to positive bins in beta transmembrane regions. Also, cation-pi interacting residues in beta transmembrane regions avoid preferring ψ-angles in the range of -59° to -30°. In this article, we insist that the studies on preferences of dihedral angles in transmembrane regions, thorough understanding of structure and folding of transmembrane proteins, can lead to modeling of novel transmembrane regions towards designing membrane proteins.
Assuntos
Alanina/química , Glicina/química , Proteínas de Membrana/química , Sequência de Aminoácidos , Modelos Moleculares , Estrutura Secundária de Proteína , TermodinâmicaRESUMO
High conservation of glycyl residues in homologous proteins is fairly frequent. It is commonly understood that glycine tends to be highly conserved either because of its unique Ramachandran angles or to avoid steric clash that would arise with a larger side chain. Using a database of aligned 3D structures of homologous proteins we identified conserved Gly in 288 alignment positions from 85 families. Ninety-six of these alignment positions correspond to conserved Gly residue with (φ, ψ) values allowed for non-glycyl residues. Reasons for this observation were investigated by in-silico mutation of these glycyl residues to Ala. We found in 94% of the cases a short contact exists between the C(ß) atom of the introduced Ala with the atoms which are often distant in the primary structure. This suggests the lack of space even for a short side chain thereby explaining high conservation of glycyl residues even when they adopt (φ, ψ) values allowed for Ala. In 189 alignment positions, the conserved glycyl residues adopt (φ, ψ) values which are disallowed for Ala. In-silico mutation of these Gly residues to Ala almost always results in steric hindrance involving C(ß) atom of Ala as one would expect by comparing Ramachandran maps for Ala and Gly. Rare occurrence of the disallowed glycyl conformations even in ultrahigh resolution protein structures are accompanied by short contacts in the crystal structures and such disallowed conformations are not conserved in the homologues. These observations raise the doubt on the accuracy of such glycyl conformations in proteins.
Assuntos
Glicina/química , Proteínas/química , Conformação Proteica , Estrutura Secundária de ProteínaRESUMO
In peptide and protein structures, occurrence of (φ,ψ) angles in the disallowed region of the Ramachandran map almost always suggests local regions of error or poor accuracy. However, very rarely genuine disallowed conformations occur as noted in the current study in proteins of known structure available at ultra-high resolution (≤1.2 Å). In the current work, extent of conservation of genuine disallowed conformations in homologous proteins of known structures has been analyzed. From a dataset of 124 protein domain families, with structure of at least one constituent member in each family available at a resolution of 1.2 Å or better, we have analyzed the conservation of 221 disallowed conformations. It is observed that the disallowed conformation is only moderately conserved in protein domain families. In the gross dataset no particular residue type adopting disallowed conformation elicit high conservation of residue type though there are alignment positions in the dataset with complete conservation of both the residue type and the disallowed conformation. Conserved disallowed conformation in protein domain families play biologically significant role in roughly 50% of the cases. The residues with the disallowed conformation or its flanking residues are often located within or around the functional site of the protein.