6 research outputs found

    Densest subgraph-based methods for protein-protein interaction hot spot prediction

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    [Background] Hot spots play an important role in protein binding analysis. The residue interaction network is a key point in hot spot prediction, and several graph theory-based methods have been proposed to detect hot spots. Although the existing methods can yield some interesting residues by network analysis, low recall has limited their abilities in finding more potential hot spots. [Result] In this study, we develop three graph theory-based methods to predict hot spots from only a single residue interaction network. We detect the important residues by finding subgraphs with high densities, i.e., high average degrees. Generally, a high degree implies a high binding possibility between protein chains, and thus a subgraph with high density usually relates to binding sites that have a high rate of hot spots. By evaluating the results on 67 complexes from the SKEMPI database, our methods clearly outperform existing graph theory-based methods on recall and F-score. In particular, our main method, Min-SDS, has an average recall of over 0.665 and an f2-score of over 0.364, while the recall and f2-score of the existing methods are less than 0.400 and 0.224, respectively. [Conclusion] The Min-SDS method performs best among all tested methods on the hot spot prediction problem, and all three of our methods provide useful approaches for analyzing bionetworks. In addition, the densest subgraph-based methods predict hot spots with only one residue interaction network, which is constructed from spatial atomic coordinate data to mitigate the shortage of data from wet-lab experiments

    The properties of human disease mutations at protein interfaces

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    The assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consideration for how this varies between different types of interfaces. Here we investigate the properties of human pathogenic and putatively benign missense variants at homomeric (isologous and heterologous), heteromeric, DNA, RNA and other ligand interfaces, and at different regions in proteins with respect to those interfaces. We find that different types of interfaces vary greatly in their propensity to be associated with pathogenic mutations, with homomeric heterologous and DNA interfaces being particularly enriched in disease. We also find that residues that do not directly participate in an interface, but are close in three-dimensional space, show a significant disease enrichment. Finally, we observe that mutations at different types of interfaces tend to have distinct property changes when undergoing amino acid substitutions associated with disease, and that this is linked to substantial variability in their identification by computational variant effect predictors

    Using machine-learning-driven approaches to boost hot-spot's knowledge

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    Understanding protein–protein interactions (PPIs) is fundamental to describe and to characterize the formation of biomolecular assemblies, and to establish the energetic principles underlying biological networks. One key aspect of these interfaces is the existence and prevalence of hot-spots (HS) residues that, upon mutation to alanine, negatively impact the formation of such protein–protein complexes. HS have been widely considered in research, both in case studies and in a few large-scale predictive approaches. This review aims to present the current knowledge on PPIs, providing a detailed understanding of the microspecifications of the residues involved in those interactions and the characteristics of those defined as HS through a thorough assessment of related field-specific methodologies. We explore recent accurate artificial intelligence-based techniques, which are progressively replacing well-established classical energy-based methodologies. This article is categorized under: Data Science > Databases and Expert Systems Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Interactions

    生物情報ネットワークのグラフ理論に基づく解析法

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    京都大学新制・課程博士博士(情報学)甲第24730号情博第818号新制||情||138(附属図書館)京都大学大学院情報学研究科知能情報学専攻(主査)教授 阿久津 達也, 教授 山本 章博, 教授 岡部 寿男学位規則第4条第1項該当Doctor of InformaticsKyoto UniversityDFA

    Investigating the Specificity of Coiled-Coil Recognition

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    The bZIP transcription factors make up a family of long α-helical proteins that dimerize based on a pattern of hydrophobic residues and bind to DNA through a region of basic residues. Because binding specificity is a particular topic of interest, the dimerization interaction is attractive as a possible candidate to better understand protein quaternary structure. Use of the Knob-Socket (KS) model for determination of packing structure provides a novel approach to analyze protein-protein interactions. A KS analysis of the protein-protein interface provides unique insight into the specificity of the classical leucine zipper pseudo-7mer repeat. From an analysis of the KS packing maps, this research provides evidence of a general framework for defining the specificity between coiled-coils. The KS maps show how hydrophobic specificity is defined in the coiled-coil interface, where knobs are centralized in the middle of the socket packing, while the peripheral socket residues are hydrophilic. Based on this KS analysis, the KS model will be used to design proteins that mimic the leucine zipper region of bZIP proteins. The proteins will be purified into E. coli and its 2º structure will be confirmed through circular dichroism. Binding specificity will be studied through mutations of the designed proteins and compared using the BACTH (bacterial adenylate cyclase two-hybrid) system
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