scholarly journals Neural Upscaling from Residue-Level Protein Structure Networks to Atomistic Structures

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1788
Author(s):  
Vy T. Duong ◽  
Elizabeth M. Diessner ◽  
Gianmarc Grazioli ◽  
Rachel W. Martin ◽  
Carter T. Butts
Keyword(s):  
Protein Structure ◽  
Intrinsically Disordered Proteins ◽  
Dynamic Models ◽  
Structural Information ◽  
Coarse Graining ◽  
Molecular Structures ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Scalable Network ◽  
Atomic Coordinates

Coarse-graining is a powerful tool for extending the reach of dynamic models of proteins and other biological macromolecules. Topological coarse-graining, in which biomolecules or sets thereof are represented via graph structures, is a particularly useful way of obtaining highly compressed representations of molecular structures, and simulations operating via such representations can achieve substantial computational savings. A drawback of coarse-graining, however, is the loss of atomistic detail—an effect that is especially acute for topological representations such as protein structure networks (PSNs). Here, we introduce an approach based on a combination of machine learning and physically-guided refinement for inferring atomic coordinates from PSNs. This “neural upscaling” procedure exploits the constraints implied by PSNs on possible configurations, as well as differences in the likelihood of observing different configurations with the same PSN. Using a 1 μs atomistic molecular dynamics trajectory of Aβ1–40, we show that neural upscaling is able to effectively recapitulate detailed structural information for intrinsically disordered proteins, being particularly successful in recovering features such as transient secondary structure. These results suggest that scalable network-based models for protein structure and dynamics may be used in settings where atomistic detail is desired, with upscaling employed to impute atomic coordinates from PSNs.

Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS

2012 ◽  
Vol 40 (5) ◽  
pp. 955-962 ◽  
Author(s):  
Nathalie Sibille ◽  
Pau Bernadó
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Dynamic Models ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Main Tool ◽  
Structural Features ◽  
Disordered Proteins ◽  
Dimensional Structure ◽  
Intrinsically Disordered ◽  
Conformational Preferences

In recent years, IDPs (intrinsically disordered proteins) have emerged as pivotal actors in biology. Despite IDPs being present in all kingdoms of life, they are more abundant in eukaryotes where they are involved in the vast majority of regulation and signalling processes. The realization that, in some cases, functional states of proteins were partly or fully disordered was in contradiction to the traditional view where a well defined three-dimensional structure was required for activity. Several experimental evidences indicate, however, that structural features in IDPs such as transient secondary-structural elements and overall dimensions are crucial to their function. NMR has been the main tool to study IDP structure by probing conformational preferences at residue level. Additionally, SAXS (small-angle X-ray scattering) has the capacity to report on the three-dimensional space sampled by disordered states and therefore complements the local information provided by NMR. The present review describes how the synergy between NMR and SAXS can be exploited to obtain more detailed structural and dynamic models of IDPs in solution. These combined strategies, embedded into computational approaches, promise the elucidation of the structure–function properties of this important, but elusive, family of biomolecules.

scholarly journals Small-angle scattering and the protein crystallographer: A relationship of ever-increasing interest

2014 ◽  
Vol 36 (1) ◽  
pp. 44-48 ◽  
Author(s):  
David J. Scott
Keyword(s):  
High Resolution ◽  
Small Angle ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
Crystallographic Analysis ◽  
Small Angle Scattering ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Angle Scattering ◽  
Relationship Of

Protein crystallography is one of the great intellectual achievements of the 20th Century, and it continues to open up new vistas of research as scientists are able to visualize in exquisite detail the molecules of Life. It has become increasingly apparent, however, that not all proteins are amenable to crystallographic analysis. These include (but are not confined to) proteins with functional flexible segments, glycoproteins and intrinsically disordered proteins. There are also proteins that, although rigid and folded, refuse to crystallize as an entire full-length construct, and hence high-resolution information has to be pieced together domain by domain. It is into this space that small-angle scattering is increasingly being used as the technique of choice with regard to attainable structural information.

scholarly journals Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 146 ◽  
Author(s):  
Supriyo Bhattacharya ◽  
Xingcheng Lin
Keyword(s):  
Single Molecule ◽  
Degrees Of Freedom ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
Conformational Dynamics ◽  
Resonance Energy ◽  
Structural Data ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Intrinsically Disordered

Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field.

scholarly journals Structure of the 5′ Untranslated Region of Enteroviral Genomic RNA

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Bejan Mahmud ◽  
Christopher M. Horn ◽  
William E. Tapprich
Keyword(s):  
Untranslated Region ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
Disordered Proteins ◽  
Type I ◽  
Genomic Rna ◽  
Entry Site ◽  
Specific Chemical ◽  
Intrinsically Disordered ◽  
Viral Virulence

ABSTRACT Enteroviral RNA genomes share a long, highly structured 5′ untranslated region (5′ UTR) containing a type I internal ribosome entry site (IRES). The 5′ UTR is composed of stably folded RNA domains connected by unstructured RNA regions. Proper folding and functioning of the 5′ UTR underlies the efficiency of viral replication and also determines viral virulence. We have characterized the structure of 5′ UTR genomic RNA from coxsackievirus B3 using selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) and base-specific chemical probes in solution. Our results revealed novel structural features, including realignment of major domains, newly identified long-range interactions, and an intrinsically disordered connecting region. Together, these newly identified features contribute to a model for enteroviral 5′ UTRs with type I IRES elements that links structure to function during the hierarchical processes directed by genomic RNA during viral infection. IMPORTANCE Enterovirus infections are responsible for human diseases, including myocarditis, pancreatitis, acute flaccid paralysis, and poliomyelitis. The virulence of these viruses depends on efficient recognition of the RNA genome by a large family of host proteins and protein synthesis factors, which in turn relies on the three-dimensional folding of the first 750 nucleotides of the molecule. Structural information about this region of the genome, called the 5′ untranslated region (5′ UTR), is needed to assist in the process of vaccine and antiviral development. This work presents a model for the structure of the enteroviral 5′ UTR. The model includes an RNA element called an intrinsically disordered RNA region (IDRR). Intrinsically disordered proteins (IDPs) are well known, but correlates in RNA have not been proposed. The proposed IDRR is a 20-nucleotide region, long known for its functional importance, where structural flexibility helps explain recognition by factors controlling multiple functional states.

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