Masanari Matsuoka

Sequence analysis on the information of folding initiation segments in ferredoxin-like fold proteins

BackgroundWhile some studies have shown that the 3D protein structures are more conservative than their amino acid sequences, other experimental studies have shown that even if two proteins share the same topology, they may have different folding pathways. There are many studies investigating this issue with molecular dynamics or Go-like model simulations, however, one should be able to obtain the same information by analyzing the proteins’ amino acid sequences, if the sequences contain all the information about the 3D structures. In this study, we use information about protein sequences to predict the location of their folding segments. We focus on proteins with a ferredoxin-like fold, which has a characteristic topology. Some of these proteins have different folding segments.ResultsDespite the simplicity of our methods, we are able to correctly determine the experimentally identified folding segments by predicting the location of the compact regions considered to play an important role in structural formation. We also apply our sequence analyses to some homologues of each protein and confirm that there are highly conserved folding segments despite the homologues’ sequence diversity. These homologues have similar folding segments even though the homology of two proteins’ sequences is not so high.ConclusionOur analyses have proven useful for investigating the common or different folding features of the proteins studied.

Analyses of Protein Sequences Using Inter-Residue Average Distance Statistics to Study Folding Processes and the Significance of Their Partial Sequences

One of the goals of molecular bioinformatics is decoding amino acid sequences to extract information on the principles of protein folding. However, this is difficult to perform with standard bioinformatics techniques such as multiple sequence alignment and so on. Thus, we propose a technique based on inter-residue average distance statistics to make predictions regarding the protein folding mechanisms of amino acid sequences. Our method involves constructing a kind of predicted contact map called an Average Distance Map (ADM) based on average distance statistics to pinpoint regions of possible folding nuclei for proteins. Only information on the amino acid sequence of a given protein is required for the present method. In this article, we summarize the results of studies using our method to analyze how specific protein sequences affect folding properties. In particular, we present studies on proteins in the phage lysozyme, such as the globin, fatty acid binding protein-like, and the cupredoxin-like fold families. In the present review, we characterize the 3D architectures of these proteins through the properties of the protein ADMs. Furthermore, we combine the information on the conserved residues within the regions predicted by the ADMs with our results obtained so far. Such information may help identify the folding characteristics of each protein. We discuss this possibility in the present review.

Topological and sequence information predict that foldons organize a partially overlapped and hierarchical structure

It has been suggested that proteins have substructures, called foldons, which can cooperatively fold into the native structure. However, several prior investigations define foldons in various ways, citing different foldon characteristics, thereby making the concept of a foldon ambiguous. In this study, we perform a Gō model simulation and analyze the characteristics of substructures that cooperatively fold into the native‐like structure. Although some results do not agree well with the experimental evidence due to the simplicity of our coarse‐grained model, our results strongly suggest that cooperatively folding units sometimes organize a partially overlapped and hierarchical structure. This view makes us easy to interpret some different proposal about the foldon as a difference of the hierarchical structure. On the basis of this finding, we present a new method to assign foldons and their hierarchy, using structural and sequence information. The results show that the foldons assigned by our method correspond to the intermediate structures identified by some experimental techniques. The new method makes it easy to predict whether a protein folds sequentially into the native structure or whether some foldons fold into the native structure in parallel. Proteins 2015; 83:1900–1913.

Implication of the cause of differences in 3D structures of proteins with high sequence identity based on analyses of amino acid sequences and 3D structures

BackgroundProteins that share a high sequence homology while exhibiting drastically different 3D structures are investigated in this study. Recently, artificial proteins related to the sequences of the GA and IgG binding GB domains of human serum albumin have been designed. These artificial proteins, referred to as GA and GB, share 98% amino acid sequence identity but exhibit different 3D structures, namely, a 3α bundle versus a 4β + α structure. Discriminating between their 3D structures based on their amino acid sequences is a very difficult problem. In the present work, in addition to using bioinformatics techniques, an analysis based on inter-residue average distance statistics is used to address this problem.ResultsIt was hard to distinguish which structure a given sequence would take only with the results of ordinary analyses like BLAST and conservation analyses. However, in addition to these analyses, with the analysis based on the inter-residue average distance statistics and our sequence tendency analysis, we could infer which part would play an important role in its structural formation.ConclusionsThe results suggest possible determinants of the different 3D structures for sequences with high sequence identity. The possibility of discriminating between the 3D structures based on the given sequences is also discussed.

Analyses of Sequences of (β/α) Barrel Proteins Based on the Inter-Residue Average Distance Statistics to Elucidate Folding Processes

It is well-known that many proteins fold into unique 3D structure (Anfinsen & Scheraga, 1975; Pain, 2000). The mechanisms by which an amino acid chain forms a complicated tertiary structure have been studied extensively (Sato et al,, 2006; Sato & Fersht, 2007; Sosnick & Barrick, 2011; Schaeffer & Daggett, 2011) but are still not understood in a comprehensive way (Bowman et al., 2011). It is well-recognized that all information on the 3D structure of a protein is coded in its amino acid sequence (Anfinsen & Scheraga, 1975; Pain, 2000). Hence we should be able to extract the information from the sequence. However, this is a significant, long-standing and unsolved problem in structural bioinformatics. Gross features of protein 3D structures or protein folds are characterized by some combination of secondary structural elements, and the ways of combination of secondary units are full of variety (Lesk, 2010). This situation does not allow us to construct a simple picture of the protein folding mechanisms. Among such a variety of protein folds, frequently appearing common folds, so-called superfolds (Orengo et al., 1994), are attractive targets for studying their folding mechanisms. The crucial point is that in general the fold of proteins tends to be more conservative than their sequences, i.e., sometimes proteins sharing the same fold show low sequence homology (Orengo et al., 1994; Jennings & Wright, 1993, Cavagnero et al., 1999; Nishimura et al., 2000). This fact implies the difficulty in approaching this problem using standard bioinformatics techniques such as multiple alignment techniques and so on.

Similar structures to the E-to-H helix unit in the globin-like fold are found in other helical folds.

A protein in the globin-like fold contains six alpha-helices, A, B, E, F, G and H. Among them, the E-to-H helix unit (E, F, G and H helices) forms a compact structure. In this study, we searched similar structures to the E-to-H helix of leghomoglobin in the whole protein structure space using the Dali program. Several similar structures were found in other helical folds, such as KaiA/RbsU domain and Type III secretion system domain. These observations suggest that the E-to-H helix unit may be a common subunit in the whole protein 3D structure space. In addition, the common conserved hydrophobic residues were found among the similar structures to the E-to-H helix unit. Hydrophobic interactions between the conserved residues may stabilize the 3D structures of the unit. We also predicted the possible compact regions of the units using the average distance method.