scholarly journals Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

2019 ◽  
Author(s):  
Hiroki Otaki ◽  
Yuzuru Taguchi ◽  
Noriyuki Nishida
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Prion Protein ◽  
Md Simulation ◽  
Structural Model ◽  
Prion Diseases ◽  
Md Simulations ◽  
Hydrophobic Residues ◽  
Prion Strains ◽  
Hydrophobic Amino Acids

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.

scholarly journals Molecular Dynamics Investigation of Phenolic Oxidative Coupling Protein Hyp-1 Derived from Hypericum perforatum

Crystals ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 43
Author(s):  
Joanna Smietanska ◽  
Tomasz Kozik ◽  
Radoslaw Strzalka ◽  
Ireneusz Buganski ◽  
Janusz Wolny
Keyword(s):  
Molecular Dynamics ◽  
Md Simulation ◽  
Hypericum Perforatum ◽  
Structural Model ◽  
Md Simulations ◽  
Atomic Displacement ◽  
Experimental Models ◽  
Coupling Protein ◽  
Atomic Displacement Parameters ◽  
Chain Conformations

Molecular dynamics (MD) simulations provide a physics-based approach to understanding protein structure and dynamics. Here, we used this intriguing tool to validate the experimental structural model of Hyp-1, a pathogenesis-related class 10 (PR-10) protein from the medicinal herb Hypericum perforatum, with potential application in various pharmaceutical therapies. A nanosecond MD simulation using the all-atom optimized potentials for liquid simulations (OPLS–AA) force field was performed to reveal that experimental atomic displacement parameters (ADPs) underestimate their values calculated from the simulation. The average structure factors obtained from the simulation confirmed to some extent the relatively high compliance of experimental and simulated Hyp-1 models. We found, however, many outliers between the experimental and simulated side-chain conformations within the Hyp-1 model, which prompted us to propose more reasonable energetically preferred rotameric forms. Therefore, we confirmed that MD simulation may be applicable for the verification of refined, experimental models and the explanation of their structural intricacies.

scholarly journals On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 99
Author(s):  
Cristian Privat ◽  
Sergio Madurga ◽  
Francesc Mas ◽  
Jaime Rubio-Martínez
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Md Simulations ◽  
Point Of View ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Protonation State ◽  
Constant Ph ◽  
Biochemical Systems ◽  
Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

scholarly journals Fully Atomistic Molecular Dynamics Computation of Physico-Mechanical Properties of PB, PS, and SBS

Nanomaterials ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 1088 ◽  
Author(s):  
Yang Kang ◽  
Dunhong Zhou ◽  
Qiang Wu ◽  
Fuyan Duan ◽  
Rufang Yao ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Strain Rate ◽  
Strain Hardening ◽  
Md Simulation ◽  
Md Simulations ◽  
Strain Rates ◽  
Young’S Moduli ◽  
Plastic Modulus ◽  
Styrene Butadiene ◽  
Butadiene Styrene

The physical properties—including density, glass transition temperature (Tg), and tensile properties—of polybutadiene (PB), polystyrene (PS) and poly (styrene-butadiene-styrene: SBS) block copolymer were predicted by using atomistic molecular dynamics (MD) simulation. At 100 K, for PB and SBS under uniaxial tension with strain rate ε ˙ = 1010 s−1 and 109 s−1, their stress–strain curves had four features, i.e., elastic, yield, softening, and strain hardening. At 300 K, the tensile curves of the three polymers with strain rates between 108 s−1 and 1010 s−1 exhibited strain hardening following elastic regime. The values of Young’s moduli of the copolymers were independent of strain rate. The plastic modulus of PS was independent of strain rate, but the Young’s moduli of PB and SBS depended on strain rate under the same conditions. After extrapolating the Young’s moduli of PB and SBS at strain rates of 0.01–1 s−1 by the linearized Eyring-like model, the predicted results by MD simulations were in accordance well with experimental results, which demonstrate that MD results are feasible for design of new materials.

scholarly journals Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras

2013 ◽  
Vol 31 (8) ◽  
pp. 829-840 ◽  
Author(s):  
Xiaojing Cong ◽  
Salvatore Bongarzone ◽  
Gabriele Giachin ◽  
Giulia Rossetti ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Prion Protein ◽  
Prion Diseases ◽  
Dominant Negative ◽  
Negative Effects ◽  
Dynamics Simulations

scholarly journals The Charge Structure of Helix 1 in the Prion Protein Regulates Conversion to Pathogenic PrPSc

2006 ◽  
Vol 80 (17) ◽  
pp. 8521-8529 ◽  
Author(s):  
Eric M. Norstrom ◽  
James A. Mastrianni
Keyword(s):  
Amino Acids ◽  
Prion Protein ◽  
Prion Diseases ◽  
Alpha Helix ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Salt Bridges ◽  
Subsequent Work ◽  
Complete Reversal ◽  
Terminal Amino

ABSTRACT The prion diseases are transmissible neurodegenerative disorders linked to a pathogenic conformer (PrPSc) of the normal prion protein (PrPC). Accumulation of PrPSc occurs via a poorly defined process in which PrPSc complexes with and converts endogenous PrPC to nascent PrPSc. Recent experiments have focused on the highly charged first alpha helix (H1) of PrP. It has been proposed that two putative asparagine-to-arginine intrahelical salt bridges stabilize H1 in PrPC yet form intermolecular ionic bonds with adjacent PrP molecules during conversion of PrPC to PrPSc (M. P. Morrissey and E. I. Shakhnovich, Proc. Natl. Acad. Sci. USA 96:11293-11298, 1999). Subsequent work (J. O. Speare et al., J. Biol. Chem. 278:12522-12529, 2003 using a cell-free assay of PrPSc conversion suggested that rather than promoting conversion, the salt bridges stabilize PrPC against it. However, the role of individual H1 charges in PrPSc generation has not yet been investigated. To approach this question, we systematically reversed or neutralized each charged residue in H1 and tested the effect on conversion to PrPSc in scrapie-infected murine neuroblastoma (ScN2a) cells. We find that replacements of charged H1 residues with like charges permit conversion, while charge reversals hinder it. Neutralization of charges in the N-terminal (amino acids 143 to 146) but not the C-terminal (amino acids 147 to 151) half of H1 permits conversion, while complete reversal of charge orientation of the putative salt bridges produces a nonconvertible PrP. Circular dichroism spectroscopy studies and confocal microscopy immunofluorescence localization studies indicated that charge substitutions did not alter the secondary structure or cell surface expression of PrPC. These data support the necessity of specific charge orientations in H1 for a productive PrPSc-PrPC complex.

A boosted unbiased molecular dynamics method for predicting ligands binding mechanisms: probing the binding pathway of dasatinib to Src-kinase

2020 ◽  
Vol 36 (18) ◽  
pp. 4714-4720
Author(s):  
Farzin Sohraby ◽  
Mostafa Javaheri Moghadam ◽  
Masoud Aliyar ◽  
Hassan Aryapour
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Md Simulation ◽  
Src Kinase ◽  
Deep Understanding ◽  
Md Simulations ◽  
Binding Mode ◽  
Supplementary Information ◽  
Computational Resources ◽  
Binding Mechanisms

Abstract Summary Small molecules such as metabolites and drugs play essential roles in biological processes and pharmaceutical industry. Knowing their interactions with biomacromolecular targets demands a deep understanding of binding mechanisms. Dozens of papers have suggested that discovering of the binding event by means of conventional unbiased molecular dynamics (MD) simulation urges considerable amount of computational resources, therefore, only one who holds a cluster or a supercomputer can afford such extensive simulations. Thus, many researchers who do not own such resources are reluctant to take the benefits of running unbiased MD simulation, in full atomistic details, when studying a ligand binding pathway. Many researchers are impelled to be content with biased MD simulations which seek its validation due to its intrinsic preconceived framework. In this work, we have presented a workable stratagem to encourage everyone to perform unbiased (unguided) MD simulations, in this case a protein–ligand binding process, by typical desktop computers and so achieve valuable results in nanosecond time scale. Here, we have described a dynamical binding’s process of an anticancer drug, the dasatinib, to the c-Src kinase in full atomistic details for the first time, without applying any biasing force or potential which may lead the drug to artificial interactions with the protein. We have attained multiple independent binding events which occurred in the nanosecond time scales, surprisingly as little as ∼30 ns. Both the protonated and deprotonated forms of the dasatinib reached the crystallographic binding mode without having any major intermediate state during induction. Availability and implementation The links of the tutorial and technical documents are accessible in the article. Supplementary information Supplementary data are available at Bioinformatics online.

Surface Tension Evaluation Via Thermodynamic Analysis of Statistical Data From Molecular Dynamics Simulations

Volume 4 ◽  
2004 ◽  
Author(s):  
Aaron P. Wemhoff ◽  
Van P. Carey
Keyword(s):  
Molecular Dynamics ◽  
Surface Tension ◽  
Density Profile ◽  
Md Simulation ◽  
Md Simulations ◽  
Bulk Liquid ◽  
Interfacial Region ◽  
Lennard Jones Potential ◽  
Jones Potential ◽  
Lennard Jones

Surface tension determination of liquid-vapor interfaces of polyatomic fluids using traditional methods has shown to be difficult due to the requirement of evaluating complex intermolecular potentials. However, analytical techniques have recently been developed that determine surface tension solely by means of the characteristics of the interfacial region between the bulk liquid and vapor regions. A post-simulation application of the excess free energy density integration (EFEDI) method was used for analysis of the resultant density profile of molecular dynamics (MD) simulations of argon using a simple Lennard-Jones potential and diatomic nitrogen using a two-center Lennard-Jones potential. MD simulations were also run for an approximation of nitrogen using the simple Lennard-Jones potential. In each MD simulation, a liquid film was initialized between vapor regions and NVE-type simulations were run to equilibrium. The simulation domain was divided into bins across the interfacial region for fluid density collection, and the resultant interfacial region density profile was used for surface tension evaluation. Application of the EFEDI method to these MD simulation results exhibited good approximations to surface tension as a function of temperature for both a simple and complex potential.

scholarly journals Neuroinvasion in Prion Diseases: The Roles of Ascending Neural Infection and Blood Dissemination

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sílvia Sisó ◽  
Lorenzo González ◽  
Martin Jeffrey
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Prion Protein ◽  
Prion Diseases ◽  
Autonomic Nerves ◽  
Peripheral Organs ◽  
Prion Strains ◽  
New Variant ◽  
Jakob Disease ◽  
The Central Nervous System

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system.

scholarly journals Nanoindentation simulations for large atomic systems : an analysis of molecular dynamics and bridged finite element - molecular dynamics methodologies

2021 ◽  
Author(s):  
Jonathan Vandersluis
Keyword(s):  
Molecular Dynamics ◽  
Finite Element ◽  
Md Simulation ◽  
Computational Simulation ◽  
Md Simulations ◽  
Single Step ◽  
Depth Interval ◽  
Simulation Tool ◽  
Custom Made ◽  
Computational Resources

This thesis develops a molecular dynamics (MD) custom made computational tool to perform nanoindentation simulations on copper nanomaterials, a Face Centred Cubic (FCC) metal. The Embedding Atom Method (EAM) is used to model the interatomic forces with the substrate. Further, a bridged finite element - molecular dynamics (FE-MD) simulation tool is also adapted to perform nanoindentation experimentation. Using this bridged FE-MD simulation tool, nanoindentations are performed much more effectively than the MD simulations while saving substantial computational simulation time. While the MD simulation experienced difficulties capturing the behaviour of the system during indentation especially at faster indentation speeds, the bridged FE-MD method is capable of reaching a state of equilibrium within a single step for each indentation depth interval analyzed throughout the nanoindentation. Although the hardness values for these simulations cannot be obtained without larger scale simulations using more powerful computational resources, the simulations provide insight into the behaviour of the copper nanomaterial during nanoindentation. As a result, it is clear that the bridged FE-MD nanoindentation tool is much more effective for executing nanoindentation simulations than the traditional MD methodologies.

scholarly journals A shift in aggregation avoidance strategy marks a long-term direction to protein evolution

2017 ◽  
Author(s):  
S.G. Foy ◽  
B.A. Wilson ◽  
J. Bertram ◽  
M.H.J. Cordes ◽  
J. Masel
Keyword(s):  
Amino Acids ◽  
Common Ancestor ◽  
Gene Families ◽  
Protein Coding ◽  
Hydrophobic Residues ◽  
Extant Species ◽  
Aggregation Problem ◽  
Hydrophobic Amino Acids ◽  
Ancestral States

AbstractTo detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years.

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