Three-dimensional Structure Of Globular Proteins Research Articles

Identifying Native and Non-native Membrane Protein Loops by Using Stabilizing Energetic Terms of Three Popular Force Fields

Background: Predicting the three-dimensional structure of globular proteins from their amino acid sequence has reached a fair accuracy, but predicting the structure of membrane proteins, especially loop regions, is still a difficult task in structural bioinformatics. The difficulty in predicting membrane loops is due to various factors like length variation, position, flexibility, and they are easily prone to mutation. Objective: In the present work, we address the problem of identifying and ranking near-native loops from a set of decoys generated by Monte-Carlo simulations. Methods: We systematically analyzed native and generated non-native decoys to develop a scoring function. The scoring function uses four important stabilizing energy terms from three popular force fields, such as FOLDX, OPLS, and AMBER, to identify and rank near-native membrane loops. Results: The results reveal better discrimination of native and non-natives and perform poor prediction in binary classifying native and near-native defined based on Root Mean Square Deviation (RMSD), Global Distance Test (GDT), and Template Modeling (TM) score, respectively. Conclusions: From our observations, we conclude that the important energy features described here may help to improve the loop prediction when the membrane protein database size increases.

The structure of the ends of α‐helices in globular proteins: Effect of additional hydrogen bonds and implications for helix formation

We prepared a set of about 2000 α-helices from a relational database of high-resolution three-dimensional structures of globular proteins, and identified additional main chain i ← i+3 hydrogen bonds at the ends of the helices (i.e., where the hydrogen bonding potential is not fulfilled by canonical i ← i+4 hydrogen bonds). About one-third of α-helices have such additional hydrogen bonds at the N-terminus, and more than half do so at the C-terminus. Although many of these additional hydrogen bonds at the C-terminus are associated with Schellman loops, the majority are not. We compared the dihedral angles at the termini of α-helices having or lacking the additional hydrogen bonds. Significant differences were found, especially at the C-terminus, where the dihedral angles at positions C2 and C1 in the absence of additional hydrogen bonds deviate substantially from those occurring within the α-helix. Using a novel approach we show how the structure of the C-terminus of the α-helix can emerge from that of constituent overlapping α-turns and β-turns, which individually show a variation in dihedral angles at different positions. We have also considered the direction of propagation of the α-helix using this approach. If one assumes that helices start as a single α-turn and grow by successive addition of further α-turns, the paths for growth in the N → C and C → N directions differ in a way that suggests that extension in the C → N direction is favored.

Statistical interior properties of globular proteins

The character of forming long-range contacts affects the three-dimensional structure of globular proteins deeply. As the different ability to form long-range contacts between 20 types of amino acids and 4 categories of globular proteins, the statistical properties are thoroughly discussed in this paper. Two parameters NC and ND are defined to confine the valid residues in detail. The relationship between hydrophobicity scales and valid residue percentage of each amino acid is given in the present work and the linear functions are shown in our statistical results. It is concluded that the hydrophobicity scale defined by chemical derivatives of the amino acids and nonpolar phase of large unilamellar vesicle membranes is the most effective technique to characterise the hydrophobic behavior of amino acid residues. Meanwhile, residue percentage Pi and sequential residue length Li of a certain protein i are calculated under different conditions. The statistical results show that the average value of Pi as well as Li of all-α proteins has a minimum among these 4 classes of globular proteins, indicating that all-α proteins are hardly capable of forming long-range contacts one by one along their linear amino acid sequences. All-β proteins have a higher tendency to construct long-range contacts along their primary sequences related to the secondary configurations, i.e. parallel and anti-parallel configurations of β sheets. The investigation of the interior properties of globular proteins give us the connection between the three-dimensional structure and its primary sequence data or secondary configurations, and help us to understand the structure of protein and its folding process well.

Evaluation of the structural quality of modeled proteins by using globularity criteria

BackgroundThe knowledge of the three-dimensional structure of globular proteins is fundamental for a detailed investigation of their functional properties. Experimental methods are too slow for structure investigation on a large scale, while computational prediction methods offer alternatives that are continuously being improved. The international Comparative Assessment of Structure Prediction (CASP), an "a posteriori" evaluation of the quality of theoretical models when the experimental structure becomes available, demonstrates that predictions can be successful as well as unsuccessful, and this suggests the necessity for evaluations able to discard "a priori" the wrong models.ResultsWe analyzed different structural properties of globular proteins for experimentally solved proteins belonging to the four different structural classes: "mainly alpha", "mainly beta", "alpha/beta" and "alpha+beta". The properties were found to be linearly correlated to protein molecular weight, but with some differences among the four classes. These results were applied to develop an evaluation test of theoretical models based on the expected globular properties of proteins. To verify the success of our test, we applied it to several protein models submitted to the sixth edition of CASP. The best theoretical models, as judged by CASP assessors, were in agreement with the expected properties, while most of the low-quality models had not passed our evaluations.ConclusionThis study supports the need for careful checks to avoid the diffusion of incorrect structural models. Our test allows the evaluation of models in the absence of experimental reference structures, thereby preventing the diffusion of incorrect structural models and the formulation of incorrect functional hypotheses. It can be used to check the globularity of predicted models, and to supplement other methods already used to evaluate their quality.

Simulations of protein folding

We have developed a simple, phenomenological, Monte-Carlo code that predicts the three-dimensional structure of globular proteins from the DNA sequences that define them. We have applied this code to two small proteins, the villin headpiece (1VII) and cole1 rop (1ROP). Our code folds both proteins to within 5 Å rms of their native structures.

The Ribbon of Hydrogen Bonds in the Three-Dimensional Structure of Globular Proteins

We report quantum mechanical computations and experimental evidence which suggest that the backbone conformation of globular proteins depends generally on the conservation of that part of the hydrogen bond network or ribbon which is joined, in general, directly to the backbone and is largely independent of the remainder of this whole network of hydrogen bonds. The familiar hydrogen bonds of the α helix and the β sheet form about one-half of this ribbon of hydrogen bonds. Both water molecules and hydrogen bonding side chain groups are involved in the formation of the ribbon.This view of the three-dimensional structure of globular proteins in terms of the `molecule' allows us to deal with the non-secondary structure as well as with the familiar secondary structure. It also suggests that the ribbon contains approximately the same number of hydrogen bonds within all three structures – the α helix, the β sheet and the coil – and that this is the reason for the ease of interconversion of these three structures.

Significance of Root-Mean-Square Deviation in Comparing Three-dimensional Structures of Globular Proteins

In the study of globular protein conformations, one customarily measures the similarity in three-dimensional structure by the root-mean-square deviation (RMSD) of the C α atomic coordinates after optimal rigid body superposition. Even when the two protein structures each consist of a single chain having the same number of residues so that the matching of C α atoms is obvious, it is not clear how to interpret the RMSD. A very large value means they are dissimilar, and zero means they are identical in conformation, but at what intermediate values are they particularly similar or clearly dissimilar? While many workers in the field have chosen arbitrary cutoffs, and others have judged values of RMSD according to the observed distribution of RMSD for random structures, we propose a self-referential, non-statistical standard. We take two conformers to be intrinsically similar if their RMSD is smaller than that when one of them is mirror inverted. Because the structures considered here are not arbitrary configurations of point atoms, but are compact, globular, polypeptide chains, our definition is closely related to similarity in radius of gyration and overall chain folding patterns. Being strongly similar in our sense implies that the radii of gyration must be nearly identical, the root-mean-square deviation in interatomic distances is linearly related to RMSD, and the two chains must have the same general fold. Only when the RMSD exceeds this level can parts of the polypeptide chain undergo nontrivial rearrangements while remaining globular. This enables us to judge when a prediction of a protein's conformation is "correct except for minor perturbations", or when the ensemble of protein structures deduced from NMR experiments are "basically in mutual agreement".

Distance-constraint approach to higher-order structures of globular proteins with empirically determined distances between amino acid residues

An analysis of higher-order structures of globular proteins by means of a distance-constraint approach is presented. Conformations are generated for each of 21 test proteins of small and medium sizes by optimizing an objective function f = sigma sigma wij(dij - (dij]2, where dij is a distance between residues i and j in a calculated conformation, (dij) is an assigned distance to the (ij) pair of residues which is determined based on the statistics of known three-dimensional structures of 14 proteins in the earlier study, and wij is a weighting factor. (dij) involves information about hydrophobicity and hydrophilicity of each amino acid residue and about connectivity of a polypeptide chain. In these calculations, only the amino acid sequence is used as input data specific to a calculated protein. With respect to higher-order structures regenerated in the optimized conformations, the following properties are analyzed: (a) N14 of a residue, defined as the number of residues surrounding the residue located within a sphere of radius of 14 A; (b) root-mean-square differences of the global and local conformations from the corresponding X-ray conformations; (c) distance profiles in the short and medium ranges; and (d) distance maps. The effects of supplementary information about locations of secondary structures and disulfide bonds are also examined to discuss the potential ability of this methodology to predict the three-dimensional structures of globular proteins.

Influences of solvent water on protein folding: free energies of solvation of cis and trans peptides are nearly identical.

Peptide bonds interact so strongly with water that even a modest difference between the free energies of solvation of their cis and trans isomers could have a significant bearing on protein structure. However, proton magnetic resonance studies at high dilution in deuteriated solvents show that N-methylformamide exists as the cis isomer to the extent of 8% in water, 10.3% in chloroform, 8.8% in benzene, and 9.2% in cyclohexane. Integrated intensities of proton and carbon resonances show that N-methylacetamide exists as the cis isomer to the extent of only 1.5% in water, not changing much in nonpolar solvents. Quantum mechanical calculations using the 6-31G basis set reproduce these relative abundances with reasonable accuracy and show that there is little difference between the dipole moments of the cis and trans isomers, for either amide. The remarkable insensitivity of cis/trans equilibria to the solvent environment and the heavy preponderance of trans isomers regardless of the polarity of the surroundings (ca. 98.5% for N-methylacetamide, whose properties may resemble those of a typical peptide bond) accord with the overwhelming preference of peptide bonds for the trans configuration that is consistently observed in the three-dimensional structures of globular proteins.

A novel and simple interpretation of the three-dimensional structure of globular proteins based on quantum mechanical computations on small model molecules. II. The clusters of myoglobin.

AbstractWe show that the bridges and clusters of the kind found earlier in rubredoxin also occur in myoglobin. The familiar acid–base(salt) bridges are at the heart of many of the clusters. The data reported by Takano [(1977) J. Mol. Biol., 110, 537–508] on sperm whale metmyoglobin reveals ten clusters together with the heme structure and some unidentified fragments. The data reported by Hanson and Schoenborn [(1981) J. Mol. Biol. 153, 117–146] on carbonmonoxymyoglobin shows numerous bridges that generally fit into the cluster picture derived from Takano's data. The data reported by S. E. V. Phillips (personal communication) on oxymyoglobin also fits into the same pattern of cluster. All but one of the myoglobin clusters are formed from two pieces of local structure each of which covers up to fifteen consecutive aminoacid residues. A “long‐range” union joins the two pieces of local structure. The clusters are generally involved with the nonhelical structure and with the junctions of the two helices. Two applications of the theory are suggested. First, the clusters offer an explanation for the formation of the α‐helices and second the unfolding of the myoglobin molecule at pH 3.8 to 5.3 is readily interpreted as the protonation at this pH of the carboxylate ions that generate the clusters that in turn support the α‐helices.

A simple and novel interpretation of the three-dimensional structure of globular proteins based on quantum-mechanical computations on small model molecules. I.

AbstractIt is suggested that the three‐dimensional structure of globular proteins is partly determined by a framework of strengthened hydrogen bonds that involves both ionic side chains and water molecules in addition to the polypeptide backbone. This conclusion follows from a combination of the results of ab initio molecular‐orbital computations on small model molecules and high‐accuracy x‐ray data on the rubredoxin molecule. The computations yield the idea of hydrogen‐bonded bridges that are built from tens of atoms, and the experimental information yields the idea that the bridges are assembled into clusters, each of which is built from hundreds of atoms. Some 10 such clusters then form a globular protein.

Dipoles of the alpha-helix and beta-sheet: their role in protein folding.

As a result of the regular arrangement of peptide dipoles in secondary structure segments and the low effective dielectric constant in Hydrophobic cores, the electrostatic energy of a protein is very sensitive to the relative orientation of the segments. We provide here evidence that the alignment of secondary structure dipoles is significant in determining the three-dimensional structure of globular proteins.

Polypeptide chain folding through a highly helical intermediate as a general principle of globular protein structure formation

General features of the three-dimensional structures of globular proteins can be explained if it is assumed that at early stages of protein folding the major part of the polypeptide chain is in the a-helical conformation [l]. Analysis of the energy, kinetics and diffusion factors as well as of the general features of the primary structure of globular proteins also suggests the formation of highly helical intermediate globule as a general principle of protein folding. In the present paper the results of such an analysis are briefly summarized. It is deduced that: (i) Short cr-helices bearing hydrophobic clusters on their surfaces must be formed first. (ii) These must then be united into a highly helical intermediate globule. (iii) A native structure must be formed by the subsequent transition of cu-helices of the highly helical intermediate globule into different types of secondary structure (this transition is not .accompanied by any considerable shifts of the material of cu-helices relative to each other). The stereochemical simulation of the formation of a highly helical intermediate and its subsequent transition into another conformation permits one to predict, in good agreement with experiment, threedimensional structures of globular proteins with different ratios of cu-helices and P-sheets [2-61 . The suggested principle of protein folding is a development of Pauling and Corey’s ideas [7] that in the absence of long-range interactions the a-helix is the most preferable conformation for a polypeptide chain. 2. Structural prerequisites

Use of random copolymers to determine the helix-coil stability constants of the naturally occurring amino acids

Abstract Short-range interactions dominate in determining the conformational preferences of the amino acid residues in proteins, and a variety of procedures (based on this concept) have been developed to predict the conformational states of the residues of a protein molecule. This paper is concerned with two such conformational states, helical and non-helical (or coil) states; the relative preferences of each of the twenty naturally occurring amino acids for these two states can be expressed in terms of the Zimm-Bragg parameters s and σ. In principle, these parameters can be determined from experimental studies of the thermally-induced helix-coil transition in homopolymers of amino acids in water. However, since most homopolyamino acids are insoluble in water, or are not helical, or (if helical) do not melt between 0 and 100°C in water, resort is had to the host-guest technique in which a random copolymer of a water-soluble host residue and a small amount of a guest residue is prepared. Using the helix-coil transition curves of such a copolymer, and the values of s and σ for the host homopolymer, it is possible to compute the values of s and σ over the temperature range of 0 – 70°C for the guest residue which is, in turn, each of the twenty naturally occurring amino acids. In most cases, the random copolymers are prepared from their N-carboxyan-hydrides, using suitable blocking groups to protect otherwise-reactive side-chain functional groups. The water-soluble copolymers are checked for the absence of racemization, α → β shifts, etc., and for the required degree of randomness. For example, for methionine as a guest residue, cyanogen bromide cleavage of the polymer chain yields a series of oligopeptides which indicates that the methionine was incorporated randomly in the chain. When the resulting values of s and σ are compared to the frequencies of occurrence of helical and non-helical conformations in proteins, a good correlation is obtained in most cases. In those cases where the correlation breaks down, the discrepancy provides information about the influence of specific long-range (e.g., electrostatic) interactions on the helical preferences of the given amino acid residues. The statistical weights deduced from the one-dimensional short-range interaction model are then incorporated with medium- and long-range interactions into a model to try to predict the three-dimensional structures of globular proteins.

Three-Dimensional Structure of Globular Proteins

Three-Dimensional Structure of Globular Proteins