On the Emergence of Orientational Order in Folded Proteins with Implications for Allostery

AbstractThe beautiful structures of single and multi-domain proteins are clearly ordered in some fashion but cannot be readily classified using group theory methods that are successfully used to describe periodic crystals. For this reason, protein structures are considered to be aperiodic, and may have evolved this way for functional purposes, especially in instances that require a combination of softness and rigidity within the same molecule. By analyzing the solved protein structures, we show that orientational symmetry is broken in the aperiodic arrangement of the secondary structural elements (SSEs), which we deduce by calculating the nematic order parameter, P2. We find that the folded structures are nematic droplets with a broad distribution of P2. We argue that non-zero values of P2, leads to an arrangement of the SSEs that can resist external stresses forces, which is a requirement for allosteric proteins. Such proteins, which resist mechanical forces in some regions while being flexible in others, transmit signals from one region of the protein to another (action at a distance) in response to binding of ligands (oxygen, ATP or other small molecules).

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On the Emergence of Orientational Order in Folded Proteins with Implications for Allostery

10.20944/preprints202103.0129.v1 ◽

2021 ◽

Author(s):

Debayan Chakraborty ◽

Mauro Lorenzo Mugnai ◽

D. Thirumalai

Keyword(s):

Orientational Order ◽

Protein Structures ◽

Mechanical Forces ◽

Structural Elements ◽

Nematic Order ◽

Allosteric Proteins ◽

Zero Values ◽

Action At A Distance ◽

Folded Proteins ◽

Folded Structures

The beautiful structures of single and multi-domain proteins are clearly ordered in some fashion but cannot be readily classified using group theory methods that are successfully used to describe periodic crystals. For this reason, protein structures are considered to be aperiodic, and may have evolved this way for functional purposes, especially in instances that require a combination of softness and rigidity within the same molecule. By analyzing the solved protein structures, we show that orientational symmetry is broken in the aperiodic arrangement of the secondary structural elements (SSEs), which we deduce by calculating the nematic order parameter, $P_2$. We find that the folded structures are nematic droplets with a broad distribution of $P_2$. We argue that non-zero values of $P_2$, leads to an arrangement of the SSEs that can resist mechanical forces, which is a requirement for allosteric proteins. Such proteins, which resist mechanical forces in some regions while being flexible in others, transmit signals from one region of the protein to another (action at a distance) in response to binding of ligands (oxygen, ATP or other small molecules).

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Probing Folded Proteins and Intact Protein Complexes by Desorption Electrospray Ionization Mass Spectrometry

10.26434/chemrxiv.12925295.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bin Yan ◽

Josephine Bunch

Keyword(s):

Mass Spectrometry ◽

Protein Complexes ◽

Protein Structures ◽

Desorption Electrospray Ionization ◽

Charge State Distribution ◽

Native Mass Spectrometry ◽

Intact Protein ◽

Ionization Mass ◽

Folded Proteins ◽

Folded Structures

Native mass spectrometry (Native MS) enables the study of intact proteins as well as non-covalent protein-protein and protein-ligand complexes in their biological state. In this work we present the application of a prototype Waters DESI source for rapid surface measurements of folded and native protein structures. Ions with narrow charge state distribution (CSD), i.e. folded structures are observed in the spectra of protein samples with the molecular weight ranging from 8.6 kDa up to 66.4 kDa. Intact protein complexes of holo-myoglobin and tetrameric hemoglobin are also successfully detected from a surface. These results reveal that DESI could be gentle enough to detect compact structures and noncovalent bond interactions. We also examine whether unfolded proteins and protein complexes can refold during transient spray solvent-sample interactions during DESI. Our results from ion mobility experiments of standards of ubiquitin, cytochrome c and protein complex myoglobin indicate that such phenomenon may occur, presenting artificial native-like spectra. Nevertheless, the observation of hemoglobin tetramer is promising as it demonstrates the capability of DESI to maintain truly native structures.

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Probing Folded Proteins and Intact Protein Complexes by Desorption Electrospray Ionization Mass Spectrometry

10.26434/chemrxiv.12925295 ◽

2020 ◽

Author(s):

Bin Yan ◽

Josephine Bunch

Keyword(s):

Mass Spectrometry ◽

Protein Complexes ◽

Protein Structures ◽

Desorption Electrospray Ionization ◽

Charge State Distribution ◽

Native Mass Spectrometry ◽

Intact Protein ◽

Ionization Mass ◽

Folded Proteins ◽

Folded Structures

Native mass spectrometry (Native MS) enables the study of intact proteins as well as non-covalent protein-protein and protein-ligand complexes in their biological state. In this work we present the application of a prototype Waters DESI source for rapid surface measurements of folded and native protein structures. Ions with narrow charge state distribution (CSD), i.e. folded structures are observed in the spectra of protein samples with the molecular weight ranging from 8.6 kDa up to 66.4 kDa. Intact protein complexes of holo-myoglobin and tetrameric hemoglobin are also successfully detected from a surface. These results reveal that DESI could be gentle enough to detect compact structures and noncovalent bond interactions. We also examine whether unfolded proteins and protein complexes can refold during transient spray solvent-sample interactions during DESI. Our results from ion mobility experiments of standards of ubiquitin, cytochrome c and protein complex myoglobin indicate that such phenomenon may occur, presenting artificial native-like spectra. Nevertheless, the observation of hemoglobin tetramer is promising as it demonstrates the capability of DESI to maintain truly native structures.

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Co-Evolution of Intrinsically Disordered Proteins with Folded Partners Witnessed by Evolutionary Couplings

International Journal of Molecular Sciences ◽

10.3390/ijms19113315 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3315 ◽

Cited By ~ 10

Author(s):

Rita Pancsa ◽

Fruzsina Zsolyomi ◽

Peter Tompa

Keyword(s):

Large Scale ◽

Intrinsically Disordered Proteins ◽

Protein Structures ◽

Disordered Proteins ◽

Cellular Interaction ◽

Structural Constraints ◽

Protein Residues ◽

Intrinsically Disordered ◽

Evolutionary Changes ◽

Folded Proteins

Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction networks, due to the lack of strict structural constraints, they undergo faster evolutionary changes than folded domains. This makes the reliable identification and alignment of IDP homologs difficult, which led to IDPs being omitted in most large-scale residue co-variation analyses. By preforming a dedicated analysis of phylogenetically widespread bacterial IDP–partner interactions, here we demonstrate that partner binding imposes constraints on IDP sequences that manifest in detectable interprotein ECs. These ECs were not detected for interactions mediated by short motifs, rather for those with larger IDP–partner interfaces. Most identified coupled residue pairs reside close (<10 Å) to each other on the interface, with a third of them forming multiple direct atomic contacts. EC-carrying interfaces of IDPs are enriched in negatively charged residues, and the EC residues of both IDPs and partners preferentially reside in helices. Our analysis brings hope that IDP–partner interactions difficult to study could soon be successfully dissected through residue co-variation analysis.

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AlphaFill: enriching the AlphaFold models with ligands and co-factors

10.1101/2021.11.26.470110 ◽

2021 ◽

Author(s):

Maarten L Hekkelman ◽

Ida de de Vries ◽

Robbie P Joosten ◽

Anastassis Perrakis

Keyword(s):

Small Molecules ◽

Structural Integrity ◽

Biological Function ◽

Protein Structures ◽

Molecular Function ◽

Structure Database ◽

Zinc Finger Motifs ◽

Structure Similarity ◽

Protein Models ◽

Design Experiments

Artificial intelligence (AI) methods for constructing structural models of proteins on the basis of their sequence are having a transformative effect in biomolecular sciences. The AlphaFold protein structure database makes available hundreds of thousands of protein structures. However, all these structures lack cofactors essential for their structural integrity and molecular function (e.g. hemoglobin lacks a bound heme), key ions essential for structural integrity (e.g. zinc-finger motifs) or catalysis (e.g. Ca2+ or Zn2+ in metalloproteases), and ligands that are important for biological function (e.g. kinase structures lack ADP or ATP). Here, we present AlphaFill, an algorithm based on sequence and structure similarity, to "transplant" such "missing" small molecules and ions from experimentally determined structures to predicted protein models. These publicly available structural annotations are mapped to predicted protein models, to help scientists interpret biological function and design experiments.

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A Bidimensional Gay-Berne Calamitic Fluid: Structure and Phase Behavior in Bulk and Strongly Confined Systems

Frontiers in Physics ◽

10.3389/fphy.2020.622872 ◽

2021 ◽

Vol 8 ◽

Author(s):

A. Calderón-Alcaraz ◽

J. Munguía-Valadez ◽

S. I. Hernández ◽

A. Ramírez-Hernández ◽

E. J. Sambriski ◽

...

Keyword(s):

Order Parameter ◽

Nematic Phase ◽

Orientational Order ◽

Topological Defects ◽

Md Simulations ◽

Structural Behavior ◽

Nematic Order ◽

Lower Temperature ◽

Geometry Characteristic ◽

Strong Confinement

A bidimensional (2D) thermotropic liquid crystal (LC) is investigated with Molecular Dynamics (MD) simulations. The Gay-Berne mesogen with parameterization GB(3, 5, 2, 1) is used to model a calamitic system. Spatial orientation of the LC samples is probed with the nematic order parameter: a sharp isotropic-smectic (I-Sm) transition is observed at lower pressures. At higher pressures, the I-Sm transition involves an intermediate nematic phase. Topology of the orthobaric phase diagram for the 2D case differs from the 3D case in two important respects: 1) the nematic region appears at lower temperatures and slightly lower densities, and 2) the critical point occurs at lower temperature and slightly higher density. The 2D calamitic model is used to probe the structural behavior of LC samples under strong confinement when either planar or homeotropic anchoring prevails. Samples subjected to circular, square, and triangular boundaries are gradually cooled to study how orientational order emerges. Depending on anchoring mode and confining geometry, characteristic topological defects emerge. Textures in these systems are similar to those observed in experiments and simulations of lyotropic LCs.

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Systematic domain-based aggregation of protein structures highlights DNA-, RNA- and other ligand-binding positions

Nucleic Acids Research ◽

10.1093/nar/gky1224 ◽

2018 ◽

Vol 47 (2) ◽

pp. 582-593 ◽

Cited By ~ 5

Author(s):

Shilpa Nadimpalli Kobren ◽

Mona Singh

Keyword(s):

Ligand Binding ◽

Small Molecules ◽

Binding Sites ◽

Protein Structures ◽

Complex Structures ◽

Disease Etiology ◽

Systematic Assessment ◽

Protein Ligand Interactions ◽

Ligand Binding Sites ◽

Ligand Interactions

Abstract Domains are fundamental subunits of proteins, and while they play major roles in facilitating protein–DNA, protein–RNA and other protein–ligand interactions, a systematic assessment of their various interaction modes is still lacking. A comprehensive resource identifying positions within domains that tend to interact with nucleic acids, small molecules and other ligands would expand our knowledge of domain functionality as well as aid in detecting ligand-binding sites within structurally uncharacterized proteins. Here, we introduce an approach to identify per-domain-position interaction ‘frequencies’ by aggregating protein co-complex structures by domain and ascertaining how often residues mapping to each domain position interact with ligands. We perform this domain-based analysis on ∼91000 co-complex structures, and infer positions involved in binding DNA, RNA, peptides, ions or small molecules across 4128 domains, which we refer to collectively as the InteracDome. Cross-validation testing reveals that ligand-binding positions for 2152 domains are highly consistent and can be used to identify residues facilitating interactions in ∼63–69% of human genes. Our resource of domain-inferred ligand-binding sites should be a great aid in understanding disease etiology: whereas these sites are enriched in Mendelian-associated and cancer somatic mutations, they are depleted in polymorphisms observed across healthy populations. The InteracDome is available at http://interacdome.princeton.edu.

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Binding site matching in rational drug design: algorithms and applications

Briefings in Bioinformatics ◽

10.1093/bib/bby078 ◽

2018 ◽

Vol 20 (6) ◽

pp. 2167-2184 ◽

Cited By ~ 3

Author(s):

Misagh Naderi ◽

Jeffrey Mitchell Lemoine ◽

Rajiv Gandhi Govindaraj ◽

Omar Zade Kana ◽

Wei Pan Feinstein ◽

...

Keyword(s):

Small Molecules ◽

Binding Site ◽

Protein Structures ◽

Chemical Properties ◽

Drug Repurposing ◽

Rational Drug Design ◽

Basic Knowledge ◽

Rational Drug ◽

Binding Pockets ◽

Local Protein

Abstract Interactions between proteins and small molecules are critical for biological functions. These interactions often occur in small cavities within protein structures, known as ligand-binding pockets. Understanding the physicochemical qualities of binding pockets is essential to improve not only our basic knowledge of biological systems, but also drug development procedures. In order to quantify similarities among pockets in terms of their geometries and chemical properties, either bound ligands can be compared to one another or binding sites can be matched directly. Both perspectives routinely take advantage of computational methods including various techniques to represent and compare small molecules as well as local protein structures. In this review, we survey 12 tools widely used to match pockets. These methods are divided into five categories based on the algorithm implemented to construct binding-site alignments. In addition to the comprehensive analysis of their algorithms, test sets and the performance of each method are described. We also discuss general pharmacological applications of computational pocket matching in drug repurposing, polypharmacology and side effects. Reflecting on the importance of these techniques in drug discovery, in the end, we elaborate on the development of more accurate meta-predictors, the incorporation of protein flexibility and the integration of powerful artificial intelligence technologies such as deep learning.

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An inertia ‘paradox’ for incompressible stratified Euler fluids

Journal of Fluid Mechanics ◽

10.1017/jfm.2012.23 ◽

2012 ◽

Vol 695 ◽

pp. 330-340 ◽

Cited By ~ 11

Author(s):

R. Camassa ◽

S. Chen ◽

G. Falqui ◽

G. Ortenzi ◽

M. Pedroni

Keyword(s):

Euler Equations ◽

Boussinesq Approximation ◽

Momentum Conservation ◽

Uniform Density ◽

Apparent Paradox ◽

Action At A Distance ◽

Horizontal Momentum ◽

Wave Models ◽

External Forces ◽

Incompressible Euler

AbstractThe interplay between incompressibility and stratification can lead to non-conservation of horizontal momentum in the dynamics of a stably stratified incompressible Euler fluid filling an infinite horizontal channel between rigid upper and lower plates. Lack of conservation occurs even though in this configuration only vertical external forces act on the system. This apparent paradox was seemingly first noticed by Benjamin (J. Fluid Mech., vol. 165, 1986, pp. 445–474) in his classification of the invariants by symmetry groups with the Hamiltonian structure of the Euler equations in two-dimensional settings, but it appears to have been largely ignored since. By working directly with the motion equations, the paradox is shown here to be a consequence of the rigid lid constraint coupling through incompressibility with the infinite inertia of the far ends of the channel, assumed to be at rest in hydrostatic equilibrium. Accordingly, when inertia is removed by eliminating the stratification, or, remarkably, by using the Boussinesq approximation of uniform density for the inertia terms, horizontal momentum conservation is recovered. This interplay between constraints, action at a distance by incompressibility, and inertia is illustrated by layer-averaged exact results, two-layer long-wave models, and direct numerical simulations of the incompressible Euler equations with smooth stratification.

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