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Biomolecules
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Computational Perspectives on Intrinsic Disorder-Based Functionality
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Computational Perspectives on Intrinsic Disorder-Based Functionality

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Bioinformatics and Systems Biology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 26660

Special Issue Editors

Prof. Dr. Vladimir N. Uversky

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Guest Editor
Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL 33612, USA
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein stability; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions; liquid-liquid phase transitions
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lukasz Kurgan

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Guest Editor
Department of Computer Science, Virginia Commonwealth University, Richmond, VA 23284, USA
Interests: structural bioinformatics; intrinsically disordered proteins; protein function prediction; protein-ligand interactions; protein-nucleic acids interactions; structural genomics
Special Issues, Collections and Topics in MDPI journals
Dr. Christopher J. Oldfield

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Guest Editor
Department of Computer Science, Virginia Commonwealth University, Richmond, VA, USA
Interests: intrinsically disordered proteins; protein bioinformatics; protein structure; protein stability; structural bioinformatics; protein-protein interactions; structural genomics

Special Issue Information

Dear Colleagues,

Proteins with intrinsically disordered regions (IDRs) are common in nature and their functions complement the functions of structured (ordered) proteins. Proteins with IDRs are involved in numerous cellular functions, such as regulation, signaling, chromosome condensation, transcription, translation, molecular assembly, and control, to name a few. Their structural flexibility enables binding to multiple partners and they often harbor molecular interaction motifs. These proteins also serve as important players controlling cellular liquid-liquid phase transitions associated with the biogenesis of various proteinaceous membrane-less organelles. While they control many biological processes, proteins with IDRs are themselves controlled and tuned by multiple mechanisms including alternative splicing and posttranslational modifications. Computational prediction and experimental analysis of the various functions of disorder are being increasingly pursued in recent years. These analyses span multiple scales, from a single region, through protein families, whole-proteomes to studies that span dozens or hundreds of proteomes.

This Special Issue of Biomolecules is dedicated to computational methods and analyses focusing on the identification, elucidation and analysis of functions of disordered proteins at all scales. We welcome both original articles and surveys that cover state-of-the-art advances in this rapidly developing area. We also encourage submission of experimental studies that are coupled with computational analysis.

Dr. Vladimir N. Uversky
Dr. Lukasz Kurgan
Dr. Christopher J. Oldfield
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • intrinsic disorder
  • intrinsically disordered proteins
  • intrinsically disordered regions
  • functions of intrinsic disorder
  • protein-protein interactions
  • protein-nucleic acids interactions
  • molecular recognition features
  • cryptic disorder
  • context-dependent disorder
  • flexible linkers
  • molecular recognition
  • molecular assembly
  • posttranslational modifications
  • alternative splicing
  • induced folding
  • protein misfolding
  • drug discovery
  • computational prediction

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Published Papers (7 papers)

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Research

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17 pages, 6303 KiB  
Article
Evolutionary Study of Disorder in Protein Sequences
by Kristina Kastano, Gábor Erdős, Pablo Mier, Gregorio Alanis-Lobato, Vasilis J. Promponas, Zsuzsanna Dosztányi and Miguel A. Andrade-Navarro
Biomolecules 2020, 10(10), 1413; https://doi.org/10.3390/biom10101413 - 6 Oct 2020
Cited by 17 | Viewed by 3752
Abstract
Intrinsically disordered proteins (IDPs) contain regions lacking intrinsic globular structure (intrinsically disordered regions, IDRs). IDPs are present across the tree of life, with great variability of IDR type and frequency even between closely related taxa. To investigate the function of IDRs, we evaluated [...] Read more.
Intrinsically disordered proteins (IDPs) contain regions lacking intrinsic globular structure (intrinsically disordered regions, IDRs). IDPs are present across the tree of life, with great variability of IDR type and frequency even between closely related taxa. To investigate the function of IDRs, we evaluated and compared the distribution of disorder content in 10,695 reference proteomes, confirming its high variability and finding certain correlation along the Euteleostomi (bony vertebrates) lineage to number of cell types. We used the comparison of orthologs to study the function of disorder related to increase in cell types, observing that multiple interacting subunits of protein complexes might gain IDRs in evolution, thus stressing the function of IDRs in modulating protein-protein interactions, particularly in the cell nucleus. Interestingly, the conservation of local compositional biases of IDPs follows residue-type specific patterns, with E- and K-rich regions being evolutionarily stable and Q- and A-rich regions being more dynamic. We provide a framework for targeted evolutionary studies of the emergence of IDRs. We believe that, given the large variability of IDR distributions in different species, studies using this evolutionary perspective are required. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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20 pages, 3822 KiB  
Article
Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain
by Arvind Ramanathan, Akash Parvatikar, Srinivas C. Chennubhotla, Yang Mei and Sangita C. Sinha
Biomolecules 2020, 10(9), 1308; https://doi.org/10.3390/biom10091308 - 11 Sep 2020
Cited by 5 | Viewed by 2365
Abstract
Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 μs) of [...] Read more.
Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 μs) of the murine γ-herpesvirus 68 vBCL2 (M11), and statistical inference techniques, we show that regions of M11 transiently unfold and refold upon binding of the BH3D. Further, we show that this partial unfolding/refolding within M11 is mediated by a network of hydrophobic interactions, which includes residues that are 10 Å away from the BH3D binding cleft. We experimentally validate the role of these hydrophobic interactions by quantifying the impact of mutating these residues on binding to the Beclin1/BECN1 BH3D, demonstrating that these mutations adversely affect both protein stability and binding. To our knowledge, this is the first study detailing the binding-associated conformational changes and presence of long-range interactions within vBCL2s. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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17 pages, 5783 KiB  
Article
Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator
by Heather M. Jeffery and Robert O. J. Weinzierl
Biomolecules 2020, 10(9), 1205; https://doi.org/10.3390/biom10091205 - 19 Aug 2020
Cited by 2 | Viewed by 3531
Abstract
The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to [...] Read more.
The human mediator subunit MED25 acts as a coactivator that binds the transcriptional activation domains (TADs) present in various cellular and viral gene-specific transcription factors. Previous studies, including on NMR measurements and site-directed mutagenesis, have only yielded low-resolution models that are difficult to refine further by experimental means. Here, we apply computational molecular dynamics simulations to study the interactions of two different TADs from the human transcription factor ETV5 (ERM) and herpes virus VP16-H1 with MED25. Like other well-studied coactivator-TAD complexes, the interactions of these intrinsically disordered domains with the coactivator surface are temporary and highly dynamic (‘fuzzy’). Due to the fact that the MED25 TAD-binding region is organized as an elongated cleft, we specifically asked whether these TADs are capable of binding in either orientation and how this could be achieved structurally and energetically. The binding of both the ETV5 and VP16-TADs in either orientation appears to be possible but occurs in a conformationally distinct manner and utilizes different sets of hydrophobic residues present in the TADs to drive the interactions. We propose that MED25 and at least a subset of human TADs specifically evolved a redundant set of molecular interaction patterns to allow binding to particular coactivators without major prior spatial constraints. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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14 pages, 2964 KiB  
Communication
Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet
by Alexandre G. de Brevern
Biomolecules 2020, 10(7), 1080; https://doi.org/10.3390/biom10071080 - 20 Jul 2020
Cited by 9 | Viewed by 3351
Abstract
Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that [...] Read more.
Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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23 pages, 3158 KiB  
Article
Sequence-Dependent Correlated Segments in the Intrinsically Disordered Region of ChiZ
by Alan Hicks, Cristian A. Escobar, Timothy A. Cross and Huan-Xiang Zhou
Biomolecules 2020, 10(6), 946; https://doi.org/10.3390/biom10060946 - 23 Jun 2020
Cited by 13 | Viewed by 3550
Abstract
How sequences of intrinsically disordered proteins (IDPs) code for their conformational dynamics is poorly understood. Here, we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. MD simulations, first validated by SAXS [...] Read more.
How sequences of intrinsically disordered proteins (IDPs) code for their conformational dynamics is poorly understood. Here, we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. MD simulations, first validated by SAXS and secondary chemical shift data, found scant α-helices or β-strands but a considerable propensity for polyproline II (PPII) torsion angles. Importantly, several blocks of residues (e.g., 11–29) emerge as “correlated segments”, identified by their frequent formation of PPII stretches, salt bridges, cation-π interactions, and sidechain-backbone hydrogen bonds. NMR relaxation experiments showed non-uniform transverse relaxation rates (R2s) and nuclear Overhauser enhancements (NOEs) along the sequence (e.g., high R2s and NOEs for residues 11–14 and 23–28). MD simulations further revealed that the extent of segmental correlation is sequence-dependent; segments where internal interactions are more prevalent manifest elevated “collective” motions on the 5–10 ns timescale and suppressed local motions on the sub-ns timescale. Amide proton exchange rates provides corroboration, with residues in the most correlated segment exhibiting the highest protection factors. We propose the correlated segment as a defining feature for the conformations and dynamics of IDPs. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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Review

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18 pages, 1682 KiB  
Review
Comparative Assessment of Intrinsic Disorder Predictions with a Focus on Protein and Nucleic Acid-Binding Proteins
by Akila Katuwawala and Lukasz Kurgan
Biomolecules 2020, 10(12), 1636; https://doi.org/10.3390/biom10121636 - 4 Dec 2020
Cited by 29 | Viewed by 3434
Abstract
With over 60 disorder predictors, users need help navigating the predictor selection task. We review 28 surveys of disorder predictors, showing that only 11 include assessment of predictive performance. We identify and address a few drawbacks of these past surveys. To this end, [...] Read more.
With over 60 disorder predictors, users need help navigating the predictor selection task. We review 28 surveys of disorder predictors, showing that only 11 include assessment of predictive performance. We identify and address a few drawbacks of these past surveys. To this end, we release a novel benchmark dataset with reduced similarity to the training sets of the considered predictors. We use this dataset to perform a first-of-its-kind comparative analysis that targets two large functional families of disordered proteins that interact with proteins and with nucleic acids. We show that limiting sequence similarity between the benchmark and the training datasets has a substantial impact on predictive performance. We also demonstrate that predictive quality is sensitive to the use of the well-annotated order and inclusion of the fully structured proteins in the benchmark datasets, both of which should be considered in future assessments. We identify three predictors that provide favorable results using the new benchmark set. While we find that VSL2B offers the most accurate and robust results overall, ESpritz-DisProt and SPOT-Disorder perform particularly well for disordered proteins. Moreover, we find that predictions for the disordered protein-binding proteins suffer low predictive quality compared to generic disordered proteins and the disordered nucleic acids-binding proteins. This can be explained by the high disorder content of the disordered protein-binding proteins, which makes it difficult for the current methods to accurately identify ordered regions in these proteins. This finding motivates the development of a new generation of methods that would target these difficult-to-predict disordered proteins. We also discuss resources that support users in collecting and identifying high-quality disorder predictions. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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16 pages, 1473 KiB  
Review
Targeting Intrinsically Disordered Proteins through Dynamic Interactions
by Jianlin Chen, Xiaorong Liu and Jianhan Chen
Biomolecules 2020, 10(5), 743; https://doi.org/10.3390/biom10050743 - 11 May 2020
Cited by 35 | Viewed by 5564
Abstract
Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design [...] Read more.
Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions. Full article
(This article belongs to the Special Issue Computational Perspectives on Intrinsic Disorder-Based Functionality)
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