Topology independent protein structural alignment

Abstract. Protein structural alignment is an indispensable tool used for many different studies in bioinformatics. Most structural alignment algorithms assume that the structural units of two similar proteins will align sequentially. This assumption may not be true for all similar proteins and as a result, proteins with similar structure but with permuted sequence arrangement are often missed. We present a solution to the problem based on an approximation algorithm that finds a sequenceorder independent structural alignment that is close to optimal. We first exhaustively fragment two proteins and calculate a novel similarity score between all possible aligned fragment pairs. We treat each aligned fragment pair as a vertex on a graph. Vertices are connected by an edge if there are intra residue sequence conflicts. We regard the realignment of the fragment pairs as a special case of the maximum-weight independent set problem and solve this computationally intensive problem approximately by iteratively solving relaxations of an appropriate integer programming formulation. The resulting structural alignment is sequence order independent. Our method is insensitive to gaps, insertions/deletions, and circular permutations.

Topological network alignment uncovers biological function and phylogeny

Sequence comparison and alignment has had an enormous impact on our understanding of evolution, biology, and disease. Comparison and alignment of biological networks will likely have a similar impact. Existing network alignments use information external to the networks, such as sequence, because no good algorithm for purely topological alignment has yet been devised. In this paper, we present a novel algorithm based solely on network topology, that can be used to align any two networks. We apply it to biological networks to produce by far the most complete topological alignments of biological networks to date. We demonstrate that both species phylogeny and detailed biological function of individual proteins can be extracted from our alignments. Topology-based alignments have the potential to provide a completely new, independent source of phylogenetic information. Our alignment of the protein-protein interaction networks of two very different species--yeast and human--indicate that even distant species share a surprising amount of network topology with each other, suggesting broad similarities in internal cellular wiring across all life on Earth.Comment: Algorithm explained in more details. Additional analysis adde

Evolution of genes and repeats in the Nimrod superfamily

The recently identified Nimrod superfamily is characterized by the presence of a special type of EGF repeat, the NIM repeat, located right after a typical CCXGY/W amino acid motif. On the basis of structural features, nimrod genes can be divided into three types. The proteins encoded by Draper-type genes have an EMI domain at the N-terminal part and only one copy of the NIM motif, followed by a variable number of EGF-like repeats. The products of Nimrod B-type and Nimrod C-type genes (including the eater gene) have different kinds of N-terminal domains, and lack EGF-like repeats but contain a variable number of NIM repeats. Draper and Nimrod C-type (but not Nimrod B-type) proteins carry a transmembrane domain. Several members of the superfamily were claimed to function as receptors in phagocytosis and/or binding of bacteria, which indicates an important role in the cellular immunity and the elimination of apoptotic cells. In this paper, the evolution of the Nimrod superfamily is studied with various methods on the level of genes and repeats. A hypothesis is presented in which the NIM repeat, along with the EMI domain, emerged by structural reorganizations at the end of an EGF-like repeat chain, suggesting a mechanism for the formation of novel types of repeats. The analyses revealed diverse evolutionary patterns in the sequences containing multiple NIM repeats. Although in the Nimrod B and Nimrod C proteins show characteristics of independent evolution, many internal NIM repeats in Eater sequences seem to have undergone concerted evolution. An analysis of the nimrod genes has been performed using phylogenetic and other methods and an evolutionary scenario of the origin and diversification of the Nimrod superfamily is proposed. Our study presents an intriguing example how the evolution of multigene families may contribute to the complexity of the innate immune response

Global Network Alignment

Motivation: High-throughput methods for detecting molecular interactions have lead to a plethora of biological network data with much more yet to come, stimulating the development of techniques for biological network alignment. Analogous to sequence alignment, efficient and reliable network alignment methods will improve our understanding of biological systems. Network alignment is computationally hard. Hence, devising efficient network alignment heuristics is currently one of the foremost challenges in computational biology. 

Results: We present a superior heuristic network alignment algorithm, called Matching-based GRAph ALigner (M-GRAAL), which can process and integrate any number and type of similarity measures between network nodes (e.g., proteins), including, but not limited to, any topological network similarity measure, sequence similarity, functional similarity, and structural similarity. This is efficient in resolving ties in similarity measures and in finding a combination of similarity measures yielding the largest biologically sound alignments. When used to align protein-protein interaction (PPI) networks of various species, M-GRAAL exposes the largest known functional and contiguous regions of network similarity. Hence, we use M-GRAAL’s alignments to predict functions of un-annotated proteins in yeast, human, and bacteria _C. jejuni_ and _E. coli_. Furthermore, using M-GRAAL to compare PPI networks of different herpes viruses, we reconstruct their phylogenetic relationship and our phylogenetic tree is the same as sequenced-based one

Structure and functional motifs of GCR1, the only plant protein with a GPCR fold?

Whether GPCRs exist in plants is a fundamental biological question. Interest in deorphanizing new G protein coupled receptors (GPCRs), arises because of their importance in signaling. Within plants, this is controversial as genome analysis has identified 56 putative GPCRs, including GCR1 which is reportedly a remote homologue to class A, B and E GPCRs. Of these, GCR2, is not a GPCR; more recently it has been proposed that none are, not even GCR1. We have addressed this disparity between genome analysis and biological evidence through a structural bioinformatics study, involving fold recognition methods, from which only GCR1 emerges as a strong candidate. To further probe GCR1, we have developed a novel helix alignment method, which has been benchmarked against the the class A – class B - class F GPCR alignments. In addition, we have presented a mutually consistent set of alignments of GCR1 homologues to class A, class B and class F GPCRs, and shown that GCR1 is closer to class A and /or class B GPCRs than class A, class B or class F GPCRs are to each other. To further probe GCR1, we have aligned transmembrane helix 3 of GCR1 to each of the 6 GPCR classes. Variability comparisons provide additional evidence that GCR1 homologues have the GPCR fold. From the alignments and a GCR1 comparative model we have identified motifs that are common to GCR1, class A, B and E GPCRs. We discuss the possibilities that emerge from this controversial evidence that GCR1 has a GPCR fol

Rampant exchange of the structure and function of extramembrane domains between membrane and water soluble proteins.

Of the membrane proteins of known structure, we found that a remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure. Moreover, 41% of known water soluble protein structures share a domain with an already known membrane protein structure. We also found that functional residues are frequently conserved between extramembrane domains of membrane and soluble proteins that share structural similarity. These results suggest membrane and soluble proteins readily exchange domains and their attendant functionalities. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. The high level of structural overlap between the two classes of proteins provides an opportunity to employ the extensive information on soluble proteins to illuminate membrane protein structure and function, for which much less is known. To this end, we employed structure guided sequence alignment to elucidate the functions of membrane proteins in the human genome. Our results bridge the gap of fold space between membrane and water soluble proteins and provide a resource for the prediction of membrane protein function. A database of predicted structural and functional relationships for proteins in the human genome is provided at sbi.postech.ac.kr/emdmp