Universal similarity measure for comparing protein structures

We introduce a new variant of the root mean square distance (RMSD) for comparing protein structures whose range of values is independent of protein size. This new dimensionless measure (relative RMSD, or RRMSD) is zero between identical structures and one between structures that are as globally dissimilar as an average pair of random polypeptides of respective sizes. The RRMSD probability distribution between random polypeptides converges to a universal curve as the chain length increases. The correlation coefficients between aligned random structures are computed as a function of polypeptide size showing two characteristic lengths of 4.7 and 37 residues. These lengths mark the separation between phases of different structural order between native protein fragments. The implications for threading are discussed.     

A new topological method to measure protein structure similarity

A method for the quantitative evaluation of structural similarity between protein pairs is developed that makes use of a Delaunay-based topological mapping. The result of the mapping is a three-dimensional array which is representative of the global structural topology and whose elements can be used to construe an integral scoring scheme. This scoring scheme was tested for its dependence on the protein length difference in a pairwise comparison, its ability to provide a reasonable means for structural similarity comparison within a family of structural neighbors of similar length, and its sensitivity to the differences in protein conformation. It is shown that such a topological evaluation of similarity is capable of providing insight into these points of interest. Protein structure comparison using the method is computationally efficient and the topological scores, although providing different information about protein similarity, correlate well with the distance root-mean-square deviation values calculated by rigid-body structural alignment.     

Recognizing misfolded and distorted protein structures by the assumption-based similarity score

A new similarity score (sigma-score) is proposed which is able to find the correct protein structure among the very close alternatives and to distinguish between correct and deliberately misfolded structures. This score is based on the general principle 'similar likes similar', and it favors hydrophobic and hydrophilic contacts, and disfavors hydrophobic-to-hydrophilic contacts in proteins. The values of sigma-scores calculated for the high-resolution protein structures from the representative set are compared with those of alternatives: (i) very close alternatives which are only slightly distorted by conformational energy minimization in vacuo; (ii) alternatives with subsequently growing distortions, generated by molecular dynamics simulations in vacuo; (iii) structures derived by molecular dynamics simulation in solvent at 300 K; (iv) deliberately misfolded protein models. In nearly all tested cases the similarity score can successfully distinguish between experimental structure and its alternatives, even if the root mean square displacement of all heavy atoms is less than 1 A. The confidence interval of the similarity score was estimated using the high-resolution X-ray structures of domain pairs related by non-crystallographic symmetry. The similarity score can be used for the evaluation of the general quality of the protein models, choosing the correct structures among the very close alternatives, characterization of models simulating folding/unfolding, etc.     

PSI: indexing protein structures for fast similarity search

MOTIVATION: We consider the problem of finding similarities in protein structure databases. Current techniques sequentially compare the given query protein to all of the proteins in the database to find similarities. Therefore, the cost of similarity queries increases linearly as the volume of the protein databases increase. As the sizes of experimentally determined and theoretically estimated protein structure databases grow, there is a need for scalable searching techniques. RESULTS: Our techniques extract feature vectors on triplets of SSEs (Secondary Structure Elements). Later, these feature vectors are indexed using a multidimensional index structure. For a given query protein, this index structure is used to quickly prune away unpromising proteins in the database. The remaining proteins are then aligned using a popular alignment tool such as VAST. We also develop a novel statistical model to estimate the goodness of a match using the SSEs. Experimental results show that our techniques improve the pruning time of VAST 3 to 3.5 times while maintaining similar sensitivity.     

Molecular docking of thiamine reveals similarity in binding properties between the prion protein and other thiamine-binding proteins

Prion-induced diseases are a global health concern. The lack of effective therapy and 100 % mortality rates for such diseases have made the prion protein an important target for drug discovery. Previous NMR experimental work revealed that thiamine and its derivatives bind the prion protein in a pocket near the N-terminal loop of helix 1, and conserved intermolecular interactions were noted between thiamine and other thiamine-binding proteins. Furthermore, water-mediated interactions were observed in all of the X-ray crystallographic structures of thiamine-binding proteins, but were not observed in the thiamine–prion NMR study. To better understand the potential role of water in thiamine–prion binding, a docking study was employed using structural X-ray solvent. Before energy minimization, docked thiamine assumed a “V” shape similar to some of the known thiamine-dependent proteins. Following minimization with NMR-derived restraints, the “F” conformation was observed. Our findings confirmed that water is involved in ligand stabilization and phosphate group interaction. The resulting refined structure of thiamine bound to the prion protein allowed the 4-aminopyrimidine ring of thiamine to π-stack with Tyr150, and facilitated hydrogen bonding between Asp147 and the amino group of 4-aminopyrimidine. Investigation of the π-stacking interaction through mutation of the tyrosine residue further revealed its importance in ligand placement. The resulting refined structure is in good agreement with previous experimental restraints, and is consistent with the pharmacophore model of thiamine-binding proteins.     

A new definition of genetic distance

Summary A stochastic measure of genetic distance between populations is proposed; unlike currently used measures, it is invariant with respect to union and subdivision of loci. This measure enables a unified quantitative approach to genetic diversity within populations and genetic distance between populations.     

Sequence similarity between protein B and human apolipoprotein A-IV

Sequence comparison of protein B (CAMP-factor) with human apolipoprotein A-IV (apo A-IV) revealed 32% similarity between the N-terminal part of protein B and a part of the putative lipid-binding domain of apo A-IV. The significance of this similarity is discussed with respect to the structure/function relationship of protein B.     

Syntheses, structures and magnetic properties of two new metal complexes based on a pyridyl-diphosphonate ligand

Two new first-raw transition metal diphosphonate complexes, namely, {[Ni₃([hpyedpH)₂(H₂O)₄]·(H₂O)₂}_n (1) and [Mn[hpyedpH₂](H₂O)]_n (2), based on a multidentate ligand 1-hydroxy-2-(3-pyridyl)-ethylidene-1,1-diphosphonic acid (hpyedpH₄) have been synthesized under hydrothermal reaction and structurally characterized by single-crystal X-ray diffraction, IR spectroscopy and element analyses. The data reveals that complex 1 is a 2D layer structure, whereas the complex 2 possesses a 1D motif. The powder X-ray diffraction (PXRD) patterns for complexes 1 and 2 were collected as well, which match well with the ones calculated from their single-crystal structure data. Magnetic measurements show that complex 1 is a ferrimagnet with T_c = 5.0 K. Magnetic studies of complex 2 indicate antiferromagnetic behavior.     

Antigenic similarity between cytoplasmic tetrodotoxin-sensitive protein and neuronal membrane proteins

Membrane proteins with a molecular weight of 290, 180, and 55 kDa were isolated using immunosorbent attached to sepharose and rabbit antibodies to cytoplasmic tetrodotoxin-sensitive protein from beef brain gray matter. A technique used for research into voltage-dependent sodium channels was applied to reconstruction of these proteins and investigation of toxin-dependent sodium flows through the lipoprotein membrane. Findings are interpreted as evidence of the similarity between cytoplasmic tetrodotoxin-sensitive protein and that of sodium channels at the cell membrane.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev; A. V. Palladin Institute of Biochemistry, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 4, pp. 485–489, July–August, 1989.     

A comprehensive analysis of non-sequential alignments between all protein structures

Background  

The majority of relations between proteins can be represented as a conventional sequential alignment. Nevertheless, unusual non-sequential alignments with different connectivity of the aligned fragments in compared proteins have been reported by many researchers. It is interesting to understand those non-sequential alignments; are they unique, sporadic cases or they occur frequently; do they belong to a few specific folds or spread among many different folds, as a common feature of protein structure. We present here a comprehensive large-scale study of non-sequential alignments between available protein structures in Protein Data Bank.     

Relation between sequence similarity and structural similarity in proteins. Role of important properties of amino acids

In a previous paper we obtained ten (orthogonal) factors, linear combinations of which can express the properties of the 20 naturally occurring amino acids. In this paper, we assume that the most important properties (linear combinations of these ten factors) that determine the three-dimensional structure of a protein are conserved properties, i.e., are those that have been conserved during evolution. Two definitions of a conserved property are presented: (1) a conserved property for an average protein is defined as that linear combination of the ten factors that optimally expresses the similarity of one amino acid to another (hence, little change during evolution), as given by the relatedness odds matrix of Dayhoff et al.; (2) a conserved property for each position in the amino acid sequence (locus) of a specific family of homologous proteins (the cytochromec family or the globin family) is defined as that linear combination of the ten factors that is common among a set of amino acids at a given locus when the sequences are properly aligned. When the specificity at each locus is averaged over all loci, the same features are observed for three expressions of these two definitions, namely the conserved property for an average protein, the average conserved property for the cytochromec family, and the average conserved property for the globin family; we find that bulk and hydrophobicity (information about packing and long-range interactions) are more important than other properties, such as the preference for adopting a specific backbone structure (information about short-range interactions). We also demonstrate that the sequence profile of a conserved property, defined for each locus of a protein family (definition 2), corresponds uniquely to the three-dimensional structure, while the conserved property for an average protein (definition 1) is not useful for the prediction of protein structure. The amino acid sequences of numerous proteins are searched to find those that are similar, in terms of the conserved properties (definition 2), to sequences of the same size from one of the homologous families (cytochromec and globin, respectively) for whose loci the conserved properties were defined. Many similar sequences are found, the number of similarities decreasing with increasing size of the segment. However, the segments must be rather long (15 residues) before the comparisons become meaningful. As an example, one sufficiently large sequence (20 residues) from a protein of known structure (apo-liver alcohol dehydrogenase that is not a member of either family) is found to be similar in the conserved properties to a particular sequence of a member of the family of human hemoglobin chains, and the two sequences have similar structures. This means that, since conserved properties are expected to be structure determinants, we can use the conserved properties to predict an initial protein structure for subsequent energy minimization for a protein for which the conserved properties are similar to those of a family of proteins with a sufficiently large number of homologous amino acid sequences; such a large number of homologous sequences is required to define a conserved property for each locus of the homologous protein family.     

Mixed-solvothermal syntheses, structures and luminescence properties of two new Zn(II) phosphonates with layered and 3D framework structures

Two new zinc phosphonates with 2-hydroxyphosphonoacetic acid (HPAA) and 1-hydroxyethylidenediphosphonic acid (hedpH₄), [Zn₂{HO₃PCH(OH)CO₂}₃]·2NH₂(CH₃)₂·3H₂O (1) and [Zn₃{CH₃C(OH)(PO₃)₂}₂]·2NH₂(CH₃)₂·H₂O (2) have been synthesized under mixed-solvothermal conditions at 160 °C and structurally characterized by X-ray single-crystal diffraction, X-ray powder diffraction, infrared spectroscopy and elemental analysis. The structure of compound 1 comprises Zn1O₆ and Zn2O₆ octahedra connected by [HO₃PCH(OH)CO₂]²⁻ to form a 2D layered structure with one-dimensional channel system along c-axis direction, and the protonated dimethylamine cations are being located between two adjacent layers. Interestingly the layers of 1 arranged in an alternative sequence (ABAB). Compound 2 features a 3D framework structure with channels along the b- and c-axis, respectively. The charge-compensating protonated Hdma⁺ cations and solvate water molecules are located inside the channels along the c-axis. A notable feature for compound 2 is the presence of the alternate left- and right-handed helical chains in the structure. The luminescence properties of compounds 1 and 2 have also been studied.     

A method for rapid similarity analysis of RNA secondary structures

Background  

Owing to the rapid expansion of RNA structure databases in recent years, efficient methods for structure comparison are in demand for function prediction and evolutionary analysis. Usually, the similarity of RNA secondary structures is evaluated based on tree models and dynamic programming algorithms. We present here a new method for the similarity analysis of RNA secondary structures.