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Liquid-liquid phase separation of α-synuclein is highly sensitive to sequence complexity

PROTEIN SCIENCE 2024年第4期33卷 e4951-e4951页

作者： Mahapatra, Anindita Newberry, Robert W. Univ Texas Austin Dept Chem 105 E 24th St Austin TX 78712 USA

The Parkinson's-associated protein alpha-synuclein (alpha-syn) can undergo liquid-liquid phase separation (LLPS), which typically leads to the formation of amyloid fibrils. The coincidence of LLPS and amyloid formation has complicated the identification of the molecular determinants unique to LLPS of alpha-syn. Moreover, the lack of strategies to selectively perturb LLPS makes it difficult to dissect the biological roles specific to alpha-syn LLPS, independent of fibrillation. Herein, using a combination of subtle missense mutations, we show that LLPS of alpha-syn is highly sensitive to its sequence complexity. In fact, we find that even a highly conservative mutation (V16I) that increases sequence complexity without perturbing physicochemical and structural properties, is sufficient to reduce LLPS by 75%;this effect can be reversed by an adjacent V-to-I mutation (V15I) that restores the original sequence complexity. A18T, a complexity-enhancing PD-associated mutation, was likewise found to reduce LLPS, implicating sequence complexity in alpha-syn pathogenicity. Furthermore, leveraging the differences in LLPS propensities among different alpha-syn variants, we demonstrate that fibrillation of alpha-syn does not necessarily correlate with its LLPS. In fact, we identify mutations that selectively perturb LLPS or fibrillation of alpha-syn, unlike previously studied mutations. The variants and design principles reported herein should therefore empower future studies to disentangle these two phenomena and distinguish their (patho)biological roles.

关键词： aggregation alpha-synuclein phase separation sequence complexity

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A look at the effect of sequence complexity on pressure destabilisation of DNA polymers

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BIOPHYSICAL CHEMISTRY 2015年 199卷 34-38页

作者： Rayan, Gamal Macgregor, Robert B., Jr. Univ Toronto Leslie Dan Fac Pharm Dept Pharmaceut Sci Toronto ON M5S 3M2 Canada

Our previous studies on the helix-coil transition of double-stranded DNA polymers have demonstrated that molar volume change (Delta V) accompanying the thermally-induced transition can be positive or negative depending on the experimental conditions, that the pressure-induced transition is more cooperative than the heat-induced transition [Rayan and Macgregor, J Phys Chem B 2005, 109, 15558-15565], and that the pressure-induced transition does not occur in the absence of water [Rayan and Macgregor, Biophys Chem, 2009, 144, 62-66]. Additionally, we have shown that Delta V values obtained by pressure-dependent techniques differ from those obtained by ambient pressure techniques such as PPC [Rayan et al. J Phys Chem B 2009, 113, 1738-1742] thus shedding light on the effects of pressure on DNA polymers. Herein, we examine the effect of sequence complexity, and hence cooperativity on pressure destabilisation of DNA polymers. Working with Clostridium perfringes DNA under conditions such that the estimated Delta V of the helix-coil transition corresponds to -1.78 mL/mol (base pair) at atmospheric pressure, we do not observe the pressure-induced helix-coil transition of this DNA polymer, whereas synthetic copolymers poly[d(A-T)] and poly[d(I-C)] undergo cooperative pressure-induced transitions at similar Delta V values. We hypothesise that the reason for the Jack of pressure-induced helix-coil transition of C perfringens DNA under these experimental conditions lies in its sequence complexity. (C) 2015 Elsevier B.V. All rights reserved.

关键词： DNA physical chemistry Helix-coil transition Pressure-denaturation Volume change sequence complexity

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Structural facets of POU2F1 in light of the functional annotations and sequence-structure patterns

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JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 2021年第3期39卷 1093-1105页

作者： Dey, Ashmita Sen, Sagnik Uversky, Vladimir N. Maulik, Ujjwal Jadavpur Univ Comp Sci & Engn Kolkata 700032 W Bengal India Russian Acad Sci Fed Res Ctr Pushchino Sci Ctr Biol Res Inst Biol Instrumentat Pushchino Moscow Region Russia Univ S Florida Dept Mol Med Morsani Coll Med Tampa FL 33620 USA Univ S Florida USF Hlth Byrd Alzheimers Res Inst Morsani Coll Med Tampa FL 33620 USA

POU domain class 2 homebox 1 or POU2F1 is broadly known as an important transcription factor. Due to its association with different types of malignancies, POU2F1 became one of the key factors in pancancer analysis. However, in spite of considering this protein as a potential drug target, none of the drug targeting POU2F1 has been designed as of yet due to the extreme structural flexibility of this protein. In this article, we have proposed a three-level comprehensive framework for understanding the structural conservation and co-variation of POU2F1. First, a gene regulatory network based on the normal and pathological functions of POU2F1 has been created for better understanding the strong association between POU2F1 deregulation and cancers. After that, based on the evolutionary sequence space analysis, the comparative sequence dynamics of the protein members of POU domain family has been studied mostly between non-human and human species. Subsequently, the reciprocity effect of the residual co-variation has been identified through direct coupling analysis. Along with that, the structure of POU2F1 has been analyzed depending on quality assessment and normal mode-based structure network. Comparing the sequence and structure space information, the most significant set of residues viz., 3, 9, 13, 17, 20, 21, 28, 35, and 36 have been identified as structural facet for function. This study demonstrates that the structural malleability of POU2F1 serves as one of the prime reason behind its functional multiplicity in terms of protein moonlighting. Communicated by Ramaswamy H. Sarma

关键词： POU domain class 2 homebox 1 gene regulatory network evolutionary trait sequence complexity predicted disorder status direct coupling analysis structural analysis and protein moonlighting property

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DNA Read Feature Importance Using Machine Learning for Read Alignment Categories 10th

DNA Read Feature Importance Using Machine Learning for Read ...

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10th International Conference on Computational Advances in Bio and Medical Sciences (ICCABS)

作者： Porter, Jacob S. Univ Virginia Biocomplex Inst & Initiat Charlottesville VA 22908 USA

ISBN: (纸本)9783030792909;9783030792893

An empirical understanding of how DNA read features affect read alignment quality categories is useful in designing better read mapping and alignment software, read trimmers, and sequence masks. Many programs appear to use arbitrarily chosen features that are putatively relevant to DNA alignment quality. Machine learning gives a ready way to empirically assess a variety of features and rank them according to their importance. sequence complexity features such as run length distribution, DUST, and entropy, and quality measures from the DNA read data were used to predict read alignment quality categories on Ion Torrent and Illumina data sets using both bisulfite-treated and untreated short DNA reads. Run length mean and variance did as well or better than the DUST score and entropy, even though several programs use the DUST score and entropy. sequence compression features performed poorly. Predictive accuracy of the models had F1-scores between 0.5-0.95 indicating that the feature set can fairly well predict alignment categories.

关键词： DNA alignment Machine learning sequence complexity

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Guessing Individual sequences: Generating Randomized Guesses Using Finite-State Machines

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IEEE TRANSACTIONS ON INFORMATION THEORY 2020年第5期66卷 2912-2920页

作者： Merhav, Neri Technion IIT Andrew & Erna Viterbi Fac Elect Engn IL-32000 Haifa Israel

Motivated by earlier results on universal randomized guessing, we consider an individual-sequence approach to the guessing problem: in this setting, the goal is to guess a secret, individual (deterministic) vector x(n) = (x(1),..., x(n)), by using a finite-state machine that sequentially generates randomized guesses from a stream of purely random bits. We define the finite-state guessing exponent as the asymptotic normalized logarithm of the minimum achievable moment of the number of randomized guesses, generated by any finite-state machine, until x(n) is guessed successfully. We show that the finite-state guessing exponent of any sequence is intimately related to its finite-state compressibility (due to Lempel and Ziv), and it is asymptotically achieved by the decoder of (a certain modified version of) the 1978 Lempel-Ziv data compression algorithm (a.k.a. the LZ78 algorithm), fed by purely random bits. The results are also extended to the case where the guessing machine has access to a side information sequence, y(n) = ( y(1),..., y(n)), which is also an individual sequence.

关键词： Guessing exponent individual sequences sequence complexity finite-state machine Lempel-Ziv algorithm incremental parsing side information randomized guessing

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An immunological glimpse of human virus peptides: Distance from self, MHC class I binding, proteasome cleveage, TAP transport and sequence composition entropy

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VIRUS RESEARCH 2022年 317卷 198814页

作者： Santoni, Daniele Felici, Giovanni Natl Res Council Italy Inst Syst Anal & Comp Sci Antonio Ruberti Via Taurini 19 I-00185 Rome Italy

Adaptive immune response is triggered when specific pathogen peptides called epitopes are recognised as exogenous according to the paradigm of self/non-self. To be recognized by immune cells, epitopes have to be exposed (presented) on the surface of the cell. Predicting if a peptide is exposed is important to shed light on the rules that govern immune response and, thus, identify potential targets and design vaccine and drugs. We focused on peptides exposed on cell surface and made accessible to immune system through the MHC Class I complex. Before this can happen, three successive selection steps have to take place: a) Proteasome cleveage, b) TAP Transport, and c) binding to MHC-class I. Starting from a set of 211 host human reference viruses, we computed the set of unique peptides occurring in the correspondent proteomes. Then, we obtained the probability values of Proteasome Cleveage, TAP Transport and Binding to MHC Class I associated to those peptides through established prediction software tools. Such values were analysed in conjunction with two other features that could play a major role: the distance from self, strictly linked to the concept of nullomers, and the sequence entropy, measuring the complexity of the peptide amino acid composition. The analysis confirmed and extended previous results on a larger, more significant and consistent data set;we showed that the higher the distances from self, the higher the score of TAP Transport and binding to MHC class I;no significant association was instead found between distance from self and Proteasome Cleveage. Additionally, amino acid peptide composition entropy was significantly associated with the other features. In particular, higher entropies were linked with higher scores of Proteasome Cleveage, TAP Transport, Binding to MHC Class I, and higher distance from self. The relationship among the three selection steps provided evidence of a tight inter-correlation, clearly suggesting it could be the product of a

关键词： Viral peptides MHC class I Immunoinformatics Self non-self sequence complexity TAP transport Proteasome cleveage

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The impact of flanking sequence features on DNA CpG methylation

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COMPUTATIONAL BIOLOGY AND CHEMISTRY 2021年 92卷 107480-107480页

作者： Santoni, Daniele Natl Res Council Italy Inst Syst Anal & Comp Sci Antonio Ruberti Via Taurini 19 I-00185 Rome Italy

Epigenetics and DNA methylation play a pivotal role in many processes of the cell and we often observe that an aberrant methylation pattern characterizes pathologies. In this work we investigate the role that the flanking sequences of CGs play in the methylation process in human. We built four different CG datasets: methylated, unmethylated, and two randomly extracted ones. We evaluated features associated to the flanking sequences of those CG sets, for different size around the CG, through five measures accounting for different aspects of sequence composition complexity and structure. The analysis performed through those measures revealed evident different behaviors between methylated and unmethylated probe sets. Major differences were observed for GC content and CG dinucleotide frequency in a window size of 300-400 bp and for CG self-attraction in 3K bp. It is remarkable as the effect of methylated CG lasts much more than expected far from the CG.

关键词： DNA methylation CpG islands Genomic sequences analysis sequence complexity G plus C genome content

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Investigating bisulfite short-read mapping failure with hairpin bisulfite sequencing data

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BMC GENOMICS 2015年第11-Sup期16卷 S2-S2页

作者： Porter, Jacob Sun, Ming-an Xie, Hehuang Zhang, Liqing Virginia Tech Dept Comp Sci Blacksburg VA 24061 USA Virginia Tech Virginia Bioinformat Inst Blacksburg VA 24061 USA Virginia Tech Dept Biol Sci Blacksburg VA 24061 USA

Background: DNA methylation is an important epigenetic mark relevant to normal development and disease genesis. A common approach to characterizing genome-wide DNA methylation is using Next Generation Sequencing technology to sequence bisulfite treated DNA. The short sequence reads are mapped to the reference genome to determine the methylation statuses of Cs. However, despite intense effort, a much smaller proportion of the reads derived from bisulfite treated DNA (usually about 40-80%) can be mapped than regular short reads mapping (> 90%), and it is unclear what factors lead to this low mapping efficiency. Results: To address this issue, we used the hairpin bisulfite sequencing technology to determine sequences of both DNA double strands simultaneously. This enabled the recovery of the original non-bisulfite-converted sequences. We used Bismark for bisulfite read mapping and Bowtie2 for recovered read mapping. We found that recovering the reads improved unique mapping efficiency by 9-10% compared to the bisulfite reads. Such improvement in mapping efficiency is related to sequence entropy. Conclusions: The hairpin recovery technique improves mapping efficiency, and sequence entropy relates to mapping efficiency.

关键词： Methylation Bisulfite short read mapping Next-generation Sequencing hairpin bisulfite data sequence complexity Entropy

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Does Lack of Secondary Structure Imply Intrinsic Disorder in Proteins? A sequence Analysis

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BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2014年第10期1844卷 1827-1834页

作者： Rani, Pooja Baruah, Anupaul Biswas, Parbati Univ Delhi Dept Chem Delhi 110007 India

Intrinsically disordered proteins (IDPs)/protein regions (IDPRs) lack unique three-dimensional structure at the level of secondary and/or tertiary structure and are represented as an ensemble of interchanging conformations. To investigate the role of presence/absence of secondary structures in promoting intrinsic disorder in proteins, a comparative sequence analysis of IDPs, IDPRs and proteins with minimal secondary structures (less than 5%) is required. A sequence analysis reveals proteins with minimal secondary structure content have high mean net positive charge, low mean net hydrophobicity and low sequence complexity. Interestingly, analysis of the relative local electrostatic interactions reveal that an increase in the relative repulsive interactions between amino acids separated by three or four residues lead to either loss of secondary structure or intrinsic disorder. IDPRs show increase in both local negative-negative and positive-positive repulsive interactions. While IDPs show a marked increase in the local negative-negative interactions, proteins with minimal secondary structure depict an increase in the local positive-positive interactions. IDPs and IDPRs are enriched in D, E and Q residues, while proteins with minimal secondary structure are depleted of these residues. Proteins with minimal secondary structures have higher content of G and C, while IDPs and IDPRs are depleted of these residues. These results confirm that proteins with minimal secondary structure have a distinctly different propensity for charge, hydrophobicity, specific amino acids and local electrostatic interactions as compared to IDPs/IDPRs. Thus we conclude that lack of secondary structure may be a necessary but not a sufficient condition for intrinsic disorder in proteins. (C) 2014 Elsevier B.V. All rights reserved.

关键词： Intrinsically disordered proteins Secondary structure sequence complexity sequence composition Charge Hydrophobicity

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Modeling and Determining Product Variety for Mass-customized Manufacturing 5th

Modeling and Determining Product Variety for Mass-customized...

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5th CIRP Conference on Assembly Technologies and Systems (CATS)

作者： Modrak, V. Marton, D. Bednar, S. Tech Univ Kosice Fac Mfg Technol Seat Presov Presov 08001 Slovakia

A great challenge facing final manufacturers of final products and OEMs today is product variety management which is crucial for mass-customized manufacturing. Product variations in most industries tend to be very numerous and firms often find themselves under pressure to solve problems with over-inventories, planning and product assembly complexity. In this paper, we investigate and present an approach to creating all possible product configurations and variations based on a given number of base components and optional number of complementary components. The idea of determining all possible product architectures is to investigate the influence of product variety on complexity of assembly processes. (C) 2014 Published by Elsevier B.V.

关键词： Configuration complexity sequence complexity Shannon's entropy Vertex degree

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