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Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the...
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Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 20958

Special Issue Editors

Dr. Luca Mollica

E-Mail Website
Guest Editor
Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Fratelli Cervi, 93, 20090 Segrate, Italy
Interests: molecular recognition; macromolecular dynamics; computational biophysical chemistry; computational aspects of molecular spectroscopy
Dr. Gabriele Giachin

E-Mail Website
Guest Editor
Department of Chemical Sciences (DiSC), University of Padua, Via F. Marzolo 1, 35131 Padova, Italy
Interests: protein misfolding diseases; mitochondrial dysfunctions; biophysical chemistry; neurodegeneration; SAXS; cryo-EM

Special Issue Information

Dear Colleagues,

Despite the widely held belief that unique biological functions of proteins require a unique three-dimensional structure, in the last twenty years, functionality has been extensively linked to molecular disorder. Experimental and computational biophysical characterization of intrinsically disordered proteins (IDPs) have demonstrated their role in several biological processes and their ability to perform unexpected tricks that are highly unlikely for ordered proteins when they interact with their partners.

Despite these advances, the study of the interaction of IDPs with their environment is still a growing field because the methods developed for characterizing or predicting interactions based on fully structured proteins are not straightforwardly applicable. In this respect, the way IDPs’ behavior is affected by specific small molecules, salts, environment crowding, changes in the pH, and/or osmolarity is still largely unclear. Moreover, molecular disorder often serves as a morphing shape-changer able to fold in different ways while binding to different partners or in the presence of different post-translational modifications, hence playing a crucial role in living systems. One recent example is the ability of IDPs to organize in the form of large assemblies (membrane-less organelles) with various functions, suggesting how IDPs serve as important regulators/hubs of molecular complex interactions.

This Special Issue of Biology, entitled “Intrinsically disordered proteins’ interactions with their molecular environments at the crossroad between theory and experiments”, aims to focus on the latest experimental and/or computational research progress in the field of IDPs/ interactions with other molecular partners and their modulation as a function of the physicochemical properties of the environment. Topics include identification, characterization and prediction of IDPs by means of advanced biophysical methods, enzymology, structural biology, and computational and mass-spectrometry approaches.

Dr. Luca Mollica
Dr. Gabriele Giachin
Guest Editors

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Keywords

  • intrinsically disordered proteins (IDPs)
  • identification
  • characterization
  • prediction
  • enzymology
  • structural biology

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Published Papers (8 papers)

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Research

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21 pages, 4593 KiB  
Article
SPEADI: Accelerated Analysis of IDP-Ion Interactions from MD-Trajectories
by Emile de Bruyn, Anton Emil Dorn, Olav Zimmermann and Giulia Rossetti
Biology 2023, 12(4), 581; https://doi.org/10.3390/biology12040581 - 10 Apr 2023
Cited by 2 | Viewed by 2270
Abstract
The disordered nature of Intrinsically Disordered Proteins (IDPs) makes their structural ensembles particularly susceptible to changes in chemical environmental conditions, often leading to an alteration of their normal functions. A Radial Distribution Function (RDF) is considered a standard method for characterizing the chemical [...] Read more.
The disordered nature of Intrinsically Disordered Proteins (IDPs) makes their structural ensembles particularly susceptible to changes in chemical environmental conditions, often leading to an alteration of their normal functions. A Radial Distribution Function (RDF) is considered a standard method for characterizing the chemical environment surrounding particles during atomistic simulations, commonly averaged over an entire or part of a trajectory. Given their high structural variability, such averaged information might not be reliable for IDPs. We introduce the Time-Resolved Radial Distribution Function (TRRDF), implemented in our open-source Python package SPEADI, which is able to characterize dynamic environments around IDPs. We use SPEADI to characterize the dynamic distribution of ions around the IDPs Alpha-Synuclein (AS) and Humanin (HN) from Molecular Dynamics (MD) simulations, and some of their selected mutants, showing that local ion–residue interactions play an important role in the structures and behaviors of IDPs. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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11 pages, 1479 KiB  
Article
How AlphaFold2 Predicts Conditionally Folding Regions Annotated in an Intrinsically Disordered Protein Database, IDEAL
by Hiroto Anbo, Koya Sakuma, Satoshi Fukuchi and Motonori Ota
Biology 2023, 12(2), 182; https://doi.org/10.3390/biology12020182 - 25 Jan 2023
Cited by 5 | Viewed by 3428
Abstract
AlphaFold2 (AF2) is a protein structure prediction program which provides accurate models. In addition to predicting structural domains, AF2 assigns intrinsically disordered regions (IDRs) by identifying regions with low prediction reliability (pLDDT). Some regions in IDRs undergo disorder-to-order transition upon binding the interaction [...] Read more.
AlphaFold2 (AF2) is a protein structure prediction program which provides accurate models. In addition to predicting structural domains, AF2 assigns intrinsically disordered regions (IDRs) by identifying regions with low prediction reliability (pLDDT). Some regions in IDRs undergo disorder-to-order transition upon binding the interaction partner. Here we assessed model structures of AF2 based on the annotations in IDEAL, in which segments with disorder-to-order transition have been collected as Protean Segments (ProSs). We non-redundantly selected ProSs from IDEAL and classified them based on the root mean square deviation to the corresponding region of AF2 models. Statistical analysis identified 11 structural and sequential features, possibly contributing toward the prediction of ProS structures. These features were categorized into two groups: one that contained pLDDT and the other that contained normalized radius of gyration. The typical ProS structures in the former group comprise a long α helix or a whole or part of the structural domain and those in the latter group comprise a short α helix with terminal loops. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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22 pages, 4669 KiB  
Article
Macromolecular Crowding Is Surprisingly Unable to Deform the Structure of a Model Biomolecular Condensate
by Julian C. Shillcock, David B. Thomas, John H. Ipsen and Andrew D. Brown
Biology 2023, 12(2), 181; https://doi.org/10.3390/biology12020181 - 25 Jan 2023
Cited by 5 | Viewed by 2975
Abstract
The crowded interior of a living cell makes performing experiments on simpler in vitro systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is [...] Read more.
The crowded interior of a living cell makes performing experiments on simpler in vitro systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is proposed to underlie the membrane-less compartmentalization of many cellular functions. How a cell reliably controls biochemical reactions in compartments open to the compositionally-varying cytoplasm is an important question for understanding cellular homeostasis. Computer simulations are often used to study the phase behavior of model biomolecular condensates, but the number of relevant parameters increases as the number of protein components increases. It is unfeasible to exhaustively simulate such models for all parameter combinations, although interesting phenomena are almost certainly hidden in their high-dimensional parameter space. Here, we have studied the phase behavior of a model biomolecular condensate in the presence of a polymeric crowding agent. We used a novel compute framework to execute dozens of simultaneous simulations spanning the protein/crowder concentration space. We then combined the results into a graphical representation for human interpretation, which provided an efficient way to search the model’s high-dimensional parameter space. We found that steric repulsion from the crowder drives a near-critical system across the phase boundary, but the molecular arrangement within the resulting biomolecular condensate is rather insensitive to the crowder concentration and molecular weight. We propose that a cell may use the local cytoplasmic concentration to assist the formation of biomolecular condensates, while relying on the dense phase to reliably provide a stable, structured, fluid milieu for cellular biochemistry despite being open to its changing environment. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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11 pages, 10272 KiB  
Article
Rapid Scan Electron Paramagnetic Resonance Spectroscopy Is a Suitable Tool to Study Intermolecular Interactions of Intrinsically Disordered Protein
by Jessica Dröden and Malte Drescher
Biology 2023, 12(1), 79; https://doi.org/10.3390/biology12010079 - 3 Jan 2023
Cited by 1 | Viewed by 1962
Abstract
Intrinsically disordered proteins (IDPs) are involved in most crucial cellular processes. However, they lack a well-defined fold hampering the investigation of their structural ensemble and interactions. Suitable biophysical methods able to manage their inherent flexibility and broad conformational ensemble are scarce. Here, we [...] Read more.
Intrinsically disordered proteins (IDPs) are involved in most crucial cellular processes. However, they lack a well-defined fold hampering the investigation of their structural ensemble and interactions. Suitable biophysical methods able to manage their inherent flexibility and broad conformational ensemble are scarce. Here, we used rapid scan (RS) electron paramagnetic resonance (EPR) spectroscopy to study the intermolecular interactions of the IDP α-synuclein (aS). aS aggregation and fibril deposition is the hallmark of Parkinson’s disease, and specific point mutations, among them A30P and A53T, were linked to the early onset of the disease. To understand the pathological processes, research intensively investigates aS aggregation kinetics, which was reported to be accelerated in the presence of ethanol. Conventional techniques fail to capture these fast processes due to their limited time resolution and, thus, lose kinetic information. We have demonstrated that RS EPR spectroscopy is suitable for studying aS aggregation by resolving underlying kinetics and highlighting differences in fibrillization behavior. RS EPR spectroscopy outperforms traditional EPR methods in terms of sensitivity by a factor of 5 in our case while significantly reducing data acquisition time. Thus, we were able to sample short time intervals capturing single events taking place during the aggregation process. Further studies will therefore be able to shed light on biological processes proceeding on fast time scales. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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12 pages, 1697 KiB  
Article
Evidence of Orientation-Dependent Early States of Prion Protein Misfolded Structures from Single Molecule Force Spectroscopy
by Andrea Raspadori, Valentina Vignali, Anna Murello, Gabriele Giachin, Bruno Samorì, Motomasa Tanaka, Carlos Bustamante, Giampaolo Zuccheri and Giuseppe Legname
Biology 2022, 11(9), 1358; https://doi.org/10.3390/biology11091358 - 16 Sep 2022
Cited by 2 | Viewed by 2516
Abstract
Prion diseases are neurodegenerative disorders characterized by the presence of oligomers and amyloid fibrils. These are the result of protein aggregation processes of the cellular prion protein (PrPC) into amyloidal forms denoted as prions or PrPSc. We employed atomic [...] Read more.
Prion diseases are neurodegenerative disorders characterized by the presence of oligomers and amyloid fibrils. These are the result of protein aggregation processes of the cellular prion protein (PrPC) into amyloidal forms denoted as prions or PrPSc. We employed atomic force microscopy (AFM) for single molecule pulling (single molecule force spectroscopy, SMFS) experiments on the recombinant truncated murine prion protein (PrP) domain to characterize its conformations and potential initial oligomerization processes. Our AFM-SMFS results point to a complex scenario of structural heterogeneity of PrP at the monomeric and dimer level, like other amyloid proteins involved in similar pathologies. By applying this technique, we revealed that the PrP C-terminal domain unfolds in a two-state process. We used two dimeric constructs with different PrP reciprocal orientations: one construct with two sequential PrP in the N- to C-terminal orientation (N-C dimer) and a second one in the C- to C-terminal orientation (C-C dimer). The analysis revealed that the different behavior in terms of unfolding force, whereby the dimer placed C-C dimer unfolds at a higher force compared to the N-C orientation. We propose that the C-C dimer orientation may represent a building block of amyloid fibril formation. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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18 pages, 3010 KiB  
Article
pH-Dependent Compaction of the Intrinsically Disordered Poly-E Motif in Titin
by Sophia Manukian, Gerrick E. Lindberg, Emily Punch, Sudarshi Premawardhana Dassanayake Mudiyanselage and Matthew J. Gage
Biology 2022, 11(9), 1302; https://doi.org/10.3390/biology11091302 - 1 Sep 2022
Cited by 3 | Viewed by 1890
Abstract
The conformational sensitivity of intrinsically disordered proteins to shifts in pH due to their high degree of charged residues has been recognized for well over a decade. However, the role of the non-ionizable residues in this pH sensitivity remains poorly understood. Our lab [...] Read more.
The conformational sensitivity of intrinsically disordered proteins to shifts in pH due to their high degree of charged residues has been recognized for well over a decade. However, the role of the non-ionizable residues in this pH sensitivity remains poorly understood. Our lab has been investigating the pH sensitivity of the poly-E motifs of the PEVK region of the muscle protein titin, which provides an ideal model system to explore this question. Using a series of 15-amino acid peptides derived from one of the poly-E motif sequences, we have investigated the role of side-chain chemistry in the conformational flexibility of this region. Our results demonstrate that aromatic side chains and proline content are the two variables that most influence pH sensitivity. The introduction of aromatic side chains resulted in a more collapsed structure, even at pH 7, while the removal of prolines resulted in a higher degree of pH sensitivity. These results highlight the importance of considering the impact of non-ionizable residues on IDP function, especially when considering the impact of pH on conformational flexibility. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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Review

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18 pages, 1675 KiB  
Review
The Action of Chemical Denaturants: From Globular to Intrinsically Disordered Proteins
by Antonella Paladino, Luigi Vitagliano and Giuseppe Graziano
Biology 2023, 12(5), 754; https://doi.org/10.3390/biology12050754 - 22 May 2023
Cited by 3 | Viewed by 2221
Abstract
Proteins perform their many functions by adopting either a minimal number of strictly similar conformations, the native state, or a vast ensemble of highly flexible conformations. In both cases, their structural features are highly influenced by the chemical environment. Even though a plethora [...] Read more.
Proteins perform their many functions by adopting either a minimal number of strictly similar conformations, the native state, or a vast ensemble of highly flexible conformations. In both cases, their structural features are highly influenced by the chemical environment. Even though a plethora of experimental studies have demonstrated the impact of chemical denaturants on protein structure, the molecular mechanism underlying their action is still debated. In the present review, after a brief recapitulation of the main experimental data on protein denaturants, we survey both classical and more recent interpretations of the molecular basis of their action. In particular, we highlight the differences and similarities of the impact that denaturants have on different structural classes of proteins, i.e., globular, intrinsically disordered (IDP), and amyloid-like assemblies. Particular attention has been given to the IDPs, as recent studies are unraveling their fundamental importance in many physiological processes. The role that computation techniques are expected to play in the near future is illustrated. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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26 pages, 7879 KiB  
Review
Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors
by Elrashdy M. Redwan, Abdullah A. Aljadawi and Vladimir N. Uversky
Biology 2022, 11(7), 1091; https://doi.org/10.3390/biology11071091 - 21 Jul 2022
Cited by 5 | Viewed by 2430
Abstract
In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered [...] Read more.
In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered from the prevalence of intrinsic disorder. Mapping of the intrinsic disorder to the HCV-TLR interactome and to the TLR-based pathways of human innate immune response to the HCV infection demonstrates that substantial levels of intrinsic disorder are characteristic for proteins involved in the regulation and execution of these innate immunity pathways and in HCV-TLR interaction. Disordered regions, being commonly enriched in sites of various posttranslational modifications, may play important functional roles by promoting protein–protein interactions and support the binding of the analyzed proteins to other partners such as nucleic acids. It seems that this system represents an important illustration of the role of intrinsic disorder in virus–host warfare. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins Interactions with Their Molecular Environment at the Crossroad between Theory and Experiments)
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