scholarly journals A Topological Selection of Folding Pathways from Native States of Knotted Proteins

Symmetry ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1670
Author(s):  
Agnese Barbensi ◽  
Naya Yerolemou ◽  
Oliver Vipond ◽  
Barbara I. Mahler ◽  
Pawel Dabrowski-Tumanski ◽  
...  
Keyword(s):  
Folding Pathway ◽  
Double Loop ◽  
Carbonic Anhydrases ◽  
And Topology ◽  
Folding Pathways ◽  
Local Symmetries ◽  
Knotted Proteins ◽  
Dynamics Simulations ◽  
Trefoil Knots ◽  
Selection Of

Understanding how knotted proteins fold is a challenging problem in biology. Researchers have proposed several models for their folding pathways, based on theory, simulations and experiments. The geometry of proteins with the same knot type can vary substantially and recent simulations reveal different folding behaviour for deeply and shallow knotted proteins. We analyse proteins forming open-ended trefoil knots by introducing a topologically inspired statistical metric that measures their entanglement. By looking directly at the geometry and topology of their native states, we are able to probe different folding pathways for such proteins. In particular, the folding pathway of shallow knotted carbonic anhydrases involves the creation of a double-looped structure, contrary to what has been observed for other knotted trefoil proteins. We validate this with Molecular Dynamics simulations. By leveraging the geometry and local symmetries of knotted proteins’ native states, we provide the first numerical evidence of a double-loop folding mechanism in trefoil proteins.

scholarly journals Unfolding and Translocation of Knotted Proteins by Clp Biological Nanomachines: Synergistic Contribution of Primary Sequence and Topology Revealed by Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Hewafonsekage Yasan Y. Fonseka ◽  
Alex Javidi ◽  
Luiz F. L. Oliveira ◽  
Cristian Micheletti ◽  
George Stan
Keyword(s):  
Molecular Dynamics ◽  
Protein Structure ◽  
Molecular Dynamics Simulations ◽  
Side Chain ◽  
Primary Sequence ◽  
Activation Barriers ◽  
And Topology ◽  
Knotted Protein ◽  
Knotted Proteins ◽  
Dynamics Simulations

AbstractWe use Langevin dynamics simulations to model, at atomistic resolution, how various natively–knotted proteins are unfolded in repeated allosteric translocating cycles of the ClpY ATPase. We consider proteins representative of different topologies, from the simplest knot (trefoil 31), to the three–twist 52 knot, to the most complex stevedore, 61, knot. We harness the atomistic detail of the simulations to address aspects that have so far remained largely unexplored, such as sequence–dependent effects on the ruggedness of the landscape traversed during knot sliding. Our simulations reveal the combined effect on translocation of the knotted protein structure, i.e. backbone topology and geometry, and primary sequence, i.e. side chain size and interactions, and show that the latter can even dominate translocation hindrance. In addition, we observe that, due to the interplay between the knotted topology and intramolecular contacts, the transmission of tension along the peptide chain occurs very differently from homopolymers. Finally, by considering native and non–native interactions, we examine how the disruption or formation of such contacts can affect the translocation processivity and concomitantly create multiple unfolding pathways with very different activation barriers.

scholarly journals Computationally Reconstructing Cotranscriptional RNA Folding Pathways from Experimental Data Reveals Rearrangement of Non-Native Folding Intermediates

2018 ◽  
Author(s):  
Angela M Yu ◽  
Paul M. Gasper ◽  
Eric J. Strobel ◽  
Kyle E. Watters ◽  
Alan A. Chen ◽  
...  
Keyword(s):  
Rna Folding ◽  
Signal Recognition Particle ◽  
Point Mutations ◽  
Structural Rearrangement ◽  
Folding Pathway ◽  
List Type ◽  
Folding Intermediates ◽  
Folding Pathways ◽  
Dynamics Simulations ◽  
Srp Rna

SummaryThe series of RNA folding events that occur during transcription, or a cotranscriptional folding pathway, can critically influence the functional roles of RNA in the cell. Here we present a method, Reconstructing RNA Dynamics from Data (R2D2), to uncover details of cotranscriptional folding pathways by predicting RNA secondary and tertiary structures from cotranscriptional SHAPE-Seq data. We applied R2D2 to the folding of the Escherichia coli Signal Recognition Particle (SRP) RNA sequence and show that this sequence undergoes folding through non-native intermediate structures that require significant structural rearrangement before reaching the functional native structure. Secondary structure folding pathway predictions and all-atom molecular dynamics simulations of folding intermediates suggest that this rearrangement can proceed through a toehold mediated strand displacement mechanism, which can be disrupted and rescued with point mutations. These results demonstrate that even RNAs with simple functional folds can undergo complex folding processes during synthesis, and that small variations in their sequence can drastically affect their cotranscriptional folding pathways.Highlights- Computational methods predict RNA structures from cotranscriptional SHAPE-Seq data- The E. coli SRP RNA folds into non-native structural intermediates cotranscriptionally- These structures rearrange dynamically to form an extended functional fold- Point mutations can disrupt and rescue cotranscriptional RNA folding pathways

Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana

2020 ◽  
Vol 16 (6) ◽  
pp. 784-795
Author(s):  
Krisnna M.A. Alves ◽  
Fábio José Bonfim Cardoso ◽  
Kathia M. Honorio ◽  
Fábio A. de Molfetta
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Point Of View ◽  
New Drugs ◽  
Leishmania Mexicana ◽  
Receptor Complexes ◽  
Starting Point ◽  
Dynamics Simulations ◽  
Selection Of

Background:: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. Objective:: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). Methods: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. Results:: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. Conclusion:: he use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

scholarly journals Comparative Assessment of NMR Probes for the Experimental Description of Protein Folding Pathways with High-Pressure NMR

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 656
Author(s):  
Vincent Van Deuren ◽  
Yin-Shan Yang ◽  
Karine de Guillen ◽  
Cécile Dubois ◽  
Catherine Anne Royer ◽  
...  
Keyword(s):  
High Pressure ◽  
Staphylococcal Nuclease ◽  
Comparative Assessment ◽  
Side Chain ◽  
Folding Pathway ◽  
Hydrophobic Core ◽  
Folding Pathways ◽  
Partial Unfolding ◽  
Protein Folding Pathways ◽  
Similar Description

Multidimensional NMR intrinsically provides multiple probes that can be used for deciphering the folding pathways of proteins: NH amide and CH groups are strategically located on the backbone of the protein, while CH3 groups, on the side-chain of methylated residues, are involved in important stabilizing interactions in the hydrophobic core. Combined with high hydrostatic pressure, these observables provide a powerful tool to explore the conformational landscapes of proteins. In the present study, we made a comparative assessment of the NH, CH, and CH3 groups for analyzing the unfolding pathway of ∆+PHS Staphylococcal Nuclease. These probes yield a similar description of the folding pathway, with virtually identical thermodynamic parameters for the unfolding reaction, despite some notable differences. Thus, if partial unfolding begins at identical pressure for these observables (especially in the case of backbone probes) and concerns similar regions of the molecule, the residues involved in contact losses are not necessarily the same. In addition, an unexpected slight shift toward higher pressure was observed in the sequence of the scenario of unfolding with CH when compared to amide groups.

scholarly journals Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Alejandro Gil L. ◽  
Pedro A. Valiente ◽  
Pedro G. Pascutti ◽  
Tirso Pons
Keyword(s):  
Structure Function ◽  
Free Energy Calculations ◽  
Special Focus ◽  
Binding Modes ◽  
Linear Interaction ◽  
Lead Compounds ◽  
Structure Function Relationship ◽  
Function Relationship ◽  
Dynamics Simulations ◽  
Selection Of

The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity.

Structures and folding pathways of topologically knotted proteins

2010 ◽  
Vol 23 (3) ◽  
pp. 033101 ◽  
Author(s):  
Peter Virnau ◽  
Anna Mallam ◽  
Sophie Jackson
Keyword(s):  
Folding Pathways ◽  
Knotted Proteins

Surface Erosion of TiO2 subjected to Energetic Oxygen Bombardment

2011 ◽  
Vol 1298 ◽  
Author(s):  
Roger Smith ◽  
Wolfhard Möller
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Atomic Clusters ◽  
Random Selection ◽  
Surface Erosion ◽  
Variable Charge ◽  
Charge Potential ◽  
Dynamics Simulations ◽  
Selection Of ◽  
Oxygen Atoms

ABSTRACTThe effect of energetic oxygen bombardment of the TiO2 rutile {110} surface is studied by means of molecular dynamics simulations using a variable charge potential. A random selection of O atoms and O2 molecules are incident successively and normally onto the surface. At an energy of 5 eV the surface becomes saturated with oxygen until covered with between 1 and 2 monolayers of adatoms. As the fluence further increases Ti atoms are pulled out from the bulk and become surrounded by the O atoms forming well-defined atomic clusters on the surface which then desorb. At bombardment energies of 400 eV, the O atoms penetrate into the bulk and voids form whose surfaces are decorated with oxygen atoms. As the O fluence further increases the surface is sputtered and the voids then intersect the surface forming a very rough topography.

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