scholarly journals A Transient Intermediate Populated in Prion Folding Leads to Domain Swapping

2019 ◽  
Author(s):  
Balaka Mondal ◽  
Govardhan Reddy
Keyword(s):  
Prion Proteins ◽  
Early Stage ◽  
Domain Swapping ◽  
Coarse Grained ◽  
Drastic Reduction ◽  
Terminal Domain ◽  
Intermediate States ◽  
Dynamics Simulations ◽  
Protein Models ◽  
Transient Intermediate

AbstractAggregation of misfolded prion proteins causes fatal neurodegenerative disorders in both humans and animals. There is an extensive effort to identify the elusive aggregation-prone conformations (N*) of prions, which are early stage precursors to aggregation. Ve studied temperature and force induced unfolding of the structured C-terminal domain of mouse (moPrP) and human prion proteins (hPrP) using molecular dynamics simulations and coarse-grained protein models. Ve find that these proteins sparsely populate intermediate states bearing the features of N* and readily undergo domain-swapped dimerization by swapping the short β-strands present at the beginning of the C-terminal domain. Structure of the N* state is similar for both moPrP and hPrP, indicating a common pathogenic precursor across diferent species. Interestingly, disease-resistant hPrP (G127V) showed a drastic reduction in the population of N* state further hinting a pathogenic connection to these partially denatured conformations. This study proposes a plausible runaway domain swapping mechanism to describe the onset of prion aggregation.

scholarly journals Double Domain Swapping in Human γC and γD Crystallin Drives Early Stages of Aggregation

2020 ◽  
Author(s):  
Balaka Mondal ◽  
Jayashree Nagesh ◽  
Govardhan Reddy
Keyword(s):  
Domain Swapping ◽  
Coarse Grained ◽  
Free Energy Surface ◽  
Early Stages ◽  
Folding Pathways ◽  
Partially Unfolded ◽  
Dynamics Simulations ◽  
Protein Models ◽  
Structural Insights

AbstractHuman γD (HγD) and γC (HγC) are double domained crystallin (Crys) proteins expressed in the nucleus of the eye lens. Structural perturbations in the protein often trigger aggregation, which eventually leads to cataract. To decipher the underlying molecular mechanism, it is important to characterize the partially unfolded conformations of Crys proteins. Using coarse grained protein models and molecular dynamics simulations, we studied the role of on-pathway folding intermediates in the early stages of aggregation. The multi-dimensional free energy surface revealed at least three different folding pathways with the population of partially structured intermediates. The two dominant pathways confirm sequential folding of the N-terminal [Ntd] and the C-terminal domains [Ctd], while the third, least favored pathway involves intermediates where both the domains are partially folded. A native like intermediate (I∗), featuring the folded domains and disrupted inter domain contacts, gets populated in all the three pathways. I∗ forms domain swapped dimers by swapping the entire Ntds and Ctds with other monomers. Population of such oligomers can explain the increased resistance to unfolding resulting in hysteresis observed in the folding experiments of HγD Crys. An ensemble of double domain swapped dimers are also formed during refolding, where intermediates consisting of partially folded Ntds and Ctds swap secondary structures with other monomers. The double domain swapping model presented in our study provides structural insights into the early events of aggregation in Crys proteins and identifies the key secondary structural swapping elements, where introducing mutations will aid in regulating the overall aggregation propensity.Abstract FigureGraphical Abstract figure

Parameterization of Divalent Cations for Coarse-Grained Simulations

2020 ◽  
Author(s):  
Florencia Klein ◽  
Daniela Cáceres-Rojas ◽  
Monica Carrasco ◽  
Juan Carlos Tapia ◽  
Julio Caballero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Metal Ions ◽  
Molecular Dynamics Simulations ◽  
Divalent Cations ◽  
Computational Cost ◽  
Data Bank ◽  
Coarse Grained ◽  
Interaction Parameters ◽  
Dynamics Simulations ◽  
Dynamical Description

<p>Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges to achieve an accurate structural and dynamical description of many biological assemblies. This is particularly the case for coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or simply not available for the vast majority of CG- force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations. Using this simple approach, we provide a set of interaction parameters for Calcium, Magnesium, and Zinc ions, which cover more than 80% of the metal-bound structures reported on the PDB. Simulations performed using the SIRAH force field on several proteins and DNA systems show that using the present approach it is possible to obtain non-bonded interaction parameters that obviate the use of topological constraints. </p>

scholarly journals Variation of Interaction Zone Size For The Target Design of 2D Supramolecular Networks

2021 ◽  
Author(s):  
Łukasz Piotr Baran ◽  
Wojciech Rżysko ◽  
Dariusz Tarasewicz
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Self Assembly ◽  
The Self ◽  
Coarse Grained ◽  
Zone Size ◽  
Interaction Zone ◽  
Supramolecular Networks ◽  
Dynamics Simulations ◽  
Target Design

In this study we have performed extensive coarse-grained molecular dynamics simulations of the self-assembly of tetra-substituted molecules. We have found that such molecules are able to form a variety of...

scholarly journals Prediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Laura Orellana ◽  
Ozge Yoluk ◽  
Oliver Carrillo ◽  
Modesto Orozco ◽  
Erik Lindahl
Keyword(s):  
Coarse Grained ◽  
Intermediate States ◽  
Coarse Grained Simulations

scholarly journals TADOSS: computational estimation of tandem domain swap stability

2018 ◽  
Vol 35 (14) ◽  
pp. 2507-2508 ◽  
Author(s):  
Aleix Lafita ◽  
Pengfei Tian ◽  
Robert B Best ◽  
Alex Bateman
Keyword(s):  
Large Scale ◽  
Domain Swapping ◽  
Coarse Grained ◽  
Supplementary Information ◽  
Simulation Studies ◽  
Computational Tools ◽  
Domain Swap ◽  
Computational Estimation ◽  
High Propensity ◽  
The Stability

Abstract Summary Proteins with highly similar tandem domains have shown an increased propensity for misfolding and aggregation. Several molecular explanations have been put forward, such as swapping of adjacent domains, but there is a lack of computational tools to systematically analyze them. We present the TAndem DOmain Swap Stability predictor (TADOSS), a method to computationally estimate the stability of tandem domain-swapped conformations from the structures of single domains, based on previous coarse-grained simulation studies. The tool is able to discriminate domains susceptible to domain swapping and to identify structural regions with high propensity to form hinge loops. TADOSS is a scalable method and suitable for large scale analyses. Availability and implementation Source code and documentation are freely available under an MIT license on GitHub at https://github.com/lafita/tadoss. Supplementary information Supplementary data are available at Bioinformatics online.

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