scholarly journals Structural and Computational Study of the GroEL–Prion Protein Complex

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1649
Author(s):  
Aleksandra A. Mamchur ◽  
Andrei V. Moiseenko ◽  
Irina S. Panina ◽  
Igor A. Yaroshevich ◽  
Sofia S. Kudryavtseva ◽  
...  

The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrPC, could lead to pathogenic transformation of the latter to the aggregation-prone PrPSc form. Here, the molecular basis of the interactions in the GroEL–PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4413
Author(s):  
Giovanny Aguilera-Durán ◽  
Antonio Romo-Mancillas

Vitiligo is a hypopigmentary skin pathology resulting from the death of melanocytes due to the activity of CD8+ cytotoxic lymphocytes and overexpression of chemokines. These include CXCL9, CXCL10, and CXCL11 and its receptor CXCR3, both in peripheral cells of the immune system and in the skin of patients diagnosed with vitiligo. The three-dimensional structure of CXCR3 and CXCL9 has not been reported experimentally; thus, homology modeling and molecular dynamics could be useful for the study of this chemotaxis-promoter axis. In this work, a homology model of CXCR3 and CXCL9 and the structure of the CXCR3/Gαi/0βγ complex with post-translational modifications of CXCR3 are reported for the study of the interaction of chemokines with CXCR3 through all-atom (AA-MD) and coarse-grained molecular dynamics (CG-MD) simulations. AA-MD and CG-MD simulations showed the first activation step of the CXCR3 receptor with all chemokines and the second activation step in the CXCR3-CXCL10 complex through a decrease in the distance between the chemokine and the transmembrane region of CXCR3 and the separation of the βγ complex from the α subunit in the G-protein. Additionally, a general protein–ligand interaction model was calculated, based on known antagonists binding to CXCR3. These results contribute to understanding the activation mechanism of CXCR3 and the design of new molecules that inhibit chemokine binding or antagonize the receptor, provoking a decrease of chemotaxis caused by the CXCR3/chemokines axis.


2008 ◽  
Vol 1074 ◽  
Author(s):  
Yun Hee Jang ◽  
François Gervais ◽  
Yves Lansac

ABSTRACTThe possibility of an A-site (La3+/Sr2+) ordering in a colossal magnetoresistance manganite (CMR) La3/4Sr1/4MnO3 was explored using molecular dynamics (MD) simulations with a newly developed force field (FF) and quantum mechanics (QM) calculations on the structures obtained from MD. The calculated degrees of stabilization (enthalpy gain) of various patterns of A-site ordering are not significant enough to overcome the accompanying entropy loss, supporting the random A-site distribution in La3/4Sr1/4MnO3. This approach combining MD and QM as well as the versatile FF developed in this study should be useful to investigate the structures and functions of magnetic tunnel junction devices involving mixed-valence manganites.


Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5853
Author(s):  
Sulejman Skoko ◽  
Matteo Ambrosetti ◽  
Tommaso Giovannini ◽  
Chiara Cappelli

We present a detailed computational study of the UV/Vis spectra of four relevant flavonoids in aqueous solution, namely luteolin, kaempferol, quercetin, and myricetin. The absorption spectra are simulated by exploiting a fully polarizable quantum mechanical (QM)/molecular mechanics (MM) model, based on the fluctuating charge (FQ) force field. Such a model is coupled with configurational sampling obtained by performing classical molecular dynamics (MD) simulations. The calculated QM/FQ spectra are compared with the experiments. We show that an accurate reproduction of the UV/Vis spectra of the selected flavonoids can be obtained by appropriately taking into account the role of configurational sampling, polarization, and hydrogen bonding interactions.


2021 ◽  
Author(s):  
Pooja Yadav ◽  
PAPIA CHOWDHURY

Abstract The virus SARS-CoV-2 has created a situation of global emergency all over the world from the last few months. We are witnessing a helpless situation due to COVID-19 as no vaccine or drug is effective against the disease. In the present study, we have tested the repurposing efficacy of some currently used combination drugs against COVID-19. We have tried to understand the mechanism of action of some repurposed drugs:Favipiravir (F), Hydroxychloroquine (H) and Oseltamivir (O). The ADME analysis have suggested strong inhibitory possibility of F, H, O combination towards receptor protein of 3CLpro of SARS-CoV-2 virus. The strong binding affinity, number of hydrogen bond interaction between inhibitor, receptor and lower inhibition constant computed from molecular docking validated the better complexation possibility of F + H + O:3CLprocombination. Various thermodynamical output from Molecular dynamics (MD) simulations like potential energy (Eg), temperature (T), density, pressure, SASA energy, interaction energies, Gibbs free energy (ΔGbind) etc., also favored the complexation between F + H + O and CoV-2 protease. Our in-silico results have recommended the strong candidature of combination drugs Favipiravir, Hydroxychloroquine and Oseltamivir as a potential lead inhibitor for targeting SARS-CoV-2 infections.


2019 ◽  
Vol 21 (35) ◽  
pp. 19327-19341 ◽  
Author(s):  
Jonas Van der Paal ◽  
Sung-Ha Hong ◽  
Maksudbek Yusupov ◽  
Nishtha Gaur ◽  
Jun-Seok Oh ◽  
...  

The combination of phospholipid vesicle experiments and molecular dynamics (MD) simulations illustrate how lipid oxidation, lipid packing and rafts formation may influence the response of healthy and diseased cell membranes to plasma-derived RONS.


2019 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida

AbstractPrions are pathogens that consist solely of abnormal isoforms of prion protein (PrPSc) without any genetic material. Therefore, they depend on purely protein-based mechanisms for diversification and maintenance of the pathogenetic information of prion strains. According to the protein-only hypothesis, the pathogenic properties of prions are determined by conformations of the constituent PrPSc, and alterations to even a single residue can drastically change the properties when the residue is located at a critical structural position of PrPSc. Interestingly, differences between polymorphic or species-specific residues responsible for the species/strain barriers are often caused by conservative replacements between hydrophobic amino acids. This implies that subtle differences among hydrophobic amino acids are significant for PrPSc structures. Specifically how the differences affect the structures is difficult to demonstrate due to the lack of detailed PrPSc structures. Here, we analyzed the influence of different hydrophobic residues on structures of an in-register parallel β-sheet amyloid of α-synuclein (αSyn) using molecular dynamics (MD) simulation, and applied the knowledge from the αSyn amyloid to design local structures of human PrPSc encompassing residues 107–143. The MD simulations of the αSyn amyloid revealed that methionine uniquely stabilized a U-shaped β-arch of the αSyn amyloid, whereas other hydrophobic amino acids destabilized the β-arch. Then, we assessed influence of the polymorphisms on the newly-designed model of PrPSc that are known to affect the clinical phenotypes of prion diseases. The MD simulations of the model also revealed unique effects of hydrophobic amino acids depending on regional structures. For example, G127V mutation that corresponds to a protective polymorphism against various human prion diseases greatly destabilized a U-shaped β-arch. Our study demonstrates specifically how and in what structures hydrophobic residues can exert unique effects on in-register parallel β-sheet amyloids and provides insights into the molecular mechanism of the strain diversity of prions and other pathogenic amyloids.Author SummaryPrions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrPSc), independently of nucleotide genome. Therefore, conformational diversity of PrPSc underlies existence of many prion strains and species barriers of prions, although the conformations still remain undetermined. As prion/PrPSc propagates through refolding the host-encoded prion protein (PrPC) into the same conformation as itself, species barriers occur when the conformation of PrPSc is incompatible with the amino acid sequence of PrPC and the nascent PrPSc cannot stably maintain the structure. Interestingly, species barriers are often caused by a difference of a single hydrophobic residue. We investigated how the subtle differences between hydrophobic amino acids affect the structural stabilities of amyloids using molecular dynamics (MD) simulation of a newly designed local structural model of PrPSc, assuming that it has in-register parallel β-sheet structures. We have found that mutations equivalent to polymorphisms that cause barriers substantially affects the stabilities; for example, G127V mutation that makes the host resistant to various human prion diseases greatly destabilized the amyloid. The results support that PrPSc is an in-register parallel β-sheet amyloid and demonstrate the usefulness of MD simulation in investigation of species barriers of prions.


2021 ◽  
Author(s):  
Subhadip Basu ◽  
Bikramjit Basu ◽  
Prabal Kumar Maiti

Protein adsorption is the first key step in cell-material interaction. The initial phase of such adsorption process can only be probed using modelling approaches like molecular dynamics (MD) simulation. Despite a large number of studies on the adsorption behaviour of proteins on different biomaterials including hydroxyapatite (HA); little attention has been paid towards quantitative assessment of the effects of various physicochemical influencers like surface modification, pH, and ionic strength. Among these factors, surface modification through isomorphic substitution of foreign ions inside the apatite structure is of particular interest in the context of protein-HA interaction as it is widely used to tailor the biological response of HA. Given this background, we present here the molecular-level understanding of fibronectin (FN) adsorption mechanism and kinetics on Sr2+-doped HA (001) surface, at 300K by means of all atom molecular dynamics simulation. Electrostatic interaction involved in adsorption of FN on HA was found to be significantly modified in presence of Sr2+ doping in apatite lattice. In harmony with the published experimental observations, the Sr-doped surface was found to better support FN adhesion compared to pure HA, with 10 mol% Sr-doped HA exhibiting best FN adsorption. Sr2+ ions also influence the stability of the secondary structure of FN, as observed from the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. The presence of Sr2+ enhances the flexibility of specific residues (residue no. 20-44, 74-88) of the FN module. Rupture forces to disentangle FN from the biomaterials surface, obtained from steered molecular dynamics (SMD) simulations, were found to corroborate well with the results of equilibrium MD simulations. One particular observation is that, the availability of RGD motif for the interaction with cell surface receptor integrin is not significantly influenced by Sr2+ substitution. Summarizing, the present work establishes a quantitative foundation towards the molecular basis of the earlier experimentally validated better cytocompatibility of Sr-doped HA.


2011 ◽  
Author(s):  
◽  
Parul Sharma

Understanding the dynamics and mechanism of protein folding continues to be one of the central problems in molecular biology. Peptide folding experiments characterize the dynamics and molecular mechanisms of the early events of protein folding. However, generally the highly flexible nature of peptides makes their bioactive conformation assessment reasonably difficult as peptides fold at very fast rates experimentally, requiring probing on the nanosecond time resolution. On the other hand, determining the bioactive conformation of biological peptides is a requirement for the design of peptidomimetics in computer-aided drug design. Peptides offer a unique opportunity to bridge the gap between theoretical and experimental understanding of protein folding. Therefore, the present work focuses on the exploration of the conformational space of biologically active neuropeptides with the aim of characterizing their conformational profile. Specifically, bombesin, neuromedin B (NMB) and neuromedin C (NMC), have been chosen for the current investigations. These peptides are widely distributed in the gastrointestinal tract, spinal cord and brain, and are known to elicit various physiological effects, including inhibition of feeding, smooth muscle contraction, exocrine and endocrine secretions, thermoregulation, blood pressure and sucrose regulations and cell growth. These peptides act as a growth factor in a wide range of tumours including carcinomas of the pancreas, stomach, breast, prostate, and colon. This work is intended to get some insight into the performance of different procedures used to explore the configurational space to provide an adequate atomic description of these systems. Different methodological studies involving utilization of molecular dynamics (MD), multicanonical replica exchange molecular dynamics (REMD) and simulate annealing (SA) are undertaken to explore the folding characteristics and thermodynamics of these neuropeptides. MD and REMD calculations on bombesin peptide have revealed its dual conformational behaviour never discovered before and is described in chapter 3. These results explain the known structure-activity studies and open the door to the understanding of the affinity of this peptide to two different receptors: BB1 and BB2. In the case of NMC, REMD calculations are carried out in explicit and implicit solvents, using the Generalized Born (GB) surface area, and are then complemented with two additional MD simulations performed using Langevin and Berendsen thermostats. The results obtained clearly reveal that REMD, performed under explicit solvent conditions, is more efficient and samples preferentially folded conformations with a higher content of  and γ turns. Moreover, these results show good agreement with the experimental results supporting the role of two -turns for its biological action, as reported in the literature. Finally, the results obtained from MD, REMD and SA calculations on NMB reveal that the peptide has a tendency to adopt both turns and helices suggesting its two different receptor recognizing and binding conformations during its biological action. Hence, the present work provides comprehensive information about the conformational preferences of neuropeptides which could lead to a better understanding of their native conformations for future investigations and point the way towards developing their new antagonists.


1999 ◽  
Vol 32 (4) ◽  
pp. 309-370 ◽  
Author(s):  
Ralph Zahn

1. Introduction 3102. Protein-only hypothesis 3123. The scrapie prion protein PrPSc3133.1 Purification of PrP 27–30 3133.2 Proteinase K resistance 3143.3 Scrapie-associated fibrils 3143.4 Smallest infectious unit 3163.5 Conformational properties 3163.6 Dissociation and stability 3194. The cellular prion protein PrPC3214.1 Prnp expression 3214.2 Biosynthetic pathway 3224.3 NMR structures 3244.4 Copper binding 3265. Post-translational PrP conversion 3275.1 Conformational isoforms 3275.2 Location of propagation 3295.3 Minimal PrP sequence 3305.4 Prion species barrier 3315.5 Prion strains 3326. Effect of familial TSE mutations 3336.1 Thermodynamic stability of PrPC 3346.2 De novo synthesis of PrPSc 3356.3 Transmembrane PrP forms 3377. Physical properties of synthetic PrP 3377.1 Amyloidogenic peptides 3377.2 Folding intermediates 3398. Hypothetical protein X 3408.1 Two species-specific epitopes 3408.2 Mapping the protein X epitope 3419. Chaperone-mediated PrP conversion 3439.1 Hsp60 and Hsp10 chaperonins 3439.2 GroEL promoted PrP-res formation 3459.3 Membrane-associated chaperonins 3459.4 Preference of GroEL for positive charges 3479.5 Potential GroEL/Hsp60 epitopes on PrP 3479.6 Conformations of chaperonin-bound PrP 3499.7 Conserved Hsp60 substrate binding sites 3499.8 Requirement of ATP-hydrolysis 3519.9 Hsp60-mediated prion propagation 35410. Template-assisted annealing model 35511. Acknowledgments 35712. References 357Although the central paradigm of protein folding (Anfinsen, 1973), that the unique three-dimensional structure of a protein is encoded in its amino acid sequence, is well established, its generality has been questioned due to two recent developments in molecular biology, the ‘prion’ and ‘molecular chaperone’. Biochemical characterization of infectious scrapie material causing central nervous system (CNS) degeneration indicates that the necessary component for disease propagation is proteinaceous (Prusiner, 1982), as first outlined by Griffith (1967) in general terms, and involves a conversion from a cellular prion protein, denoted PrPC, into a toxic scrapie form, PrPSc, which is facilitated by PrPSc acting as a template for PrPC to form new PrPSc molecules (Prusiner, 1987). The ‘protein-only’ hypothesis implies that the same polypeptide sequence, in the absence of any post-translational modifications, can adopt two considerably different stable protein conformations (Fig. 1). Thus, in the case of prions it is possible, although not proven, that they violate the central paradigm of protein folding. There is some indirect evidence that another factor, provisionally named ‘protein X’, might be involved in the conformational conversion process (Prusiner et al. 1998), which includes a dramatic change from α-helical into β-sheet secondary structure (Fig. 1). This factor has not been identified yet, but it has been proposed that protein X may act as a molecular chaperone. The idea that molecular chaperones play a critical role in the generation of PrPSc is appealing also from a theoretical point of view, because PrPSc formation involves changes in protein folding and possibly intermolecular aggregation (Fig. 1), processes in which chaperones are known to participate (Musgrove & Ellis, 1986). The discovery and functional analysis of more than a dozen molecular chaperones made it clear that these proteins do not complement folding information that is not already contained in the genetic code (Ellis et al. 1989); rather they facilitate the folding and assembly of proteins by preventing misfolding and refolding misfolded proteins (Hartl, 1996). Whether a molecular chaperone or another type of macromolecule is identified as the conversion factor, therefore, the molecular chaperone concept is likely to contribute to the understanding of the molecular nature of PrPC to PrPSc conversion.In this review I consider the prion concept from the view of a structural biologist whose main interest focuses on spontaneous and chaperone-mediated conformational changes in proteins.


2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden

AbstractFixed and induced point dipoles have been implemented in the Ewald and Particle-Mesh Ewald (PME) formalisms. During molecular dynamics (MD) the induced dipoles can be propagated along with the atomic positions either by interation to self-consistency at each time step, or by a Car-Parrinello (CP) technique using an extended Lagrangian formalism. The use of PME for electrostatics of fixed charges and induced dipoles together with a CP treatment of dipole propagation in MD simulations leads to a cost overhead of only 33% above that of MD simulations using standard PME with fixed charges, allowing the study of polarizability in largemacromolecular systems.


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