Quantifying the role of interface atomic structure in the compressive response of Ti2AlN/TiAl composite using MD simulations

We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of MgA2+ are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of MgA2+ does not include the Oδ1 atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O3'H3' group in ATP to Asp440 via a shuttling water molecule and PA-O3A bond cleavage and O3'-PA bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, MgA2+ is bound to the Oδ1(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O3'H3' group via shuttling water molecules.

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Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

Cell Discovery ◽

10.1038/s41421-021-00259-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sensen Zhang ◽

Baolei Yuan ◽

Jordy Homing Lam ◽

Jun Zhou ◽

Xuan Zhou ◽

...

Keyword(s):

Md Simulation ◽

Potential Role ◽

Md Simulations ◽

Full Length ◽

Inflammasome Activation ◽

Simulation Studies ◽

Cryo Electron Microscopy ◽

Gating Mechanism ◽

Atp Efflux

AbstractPannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.

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Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Scientific Reports ◽

10.1038/s41598-020-80524-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mei Dang ◽

Yifan Li ◽

Jianxing Song

Keyword(s):

Conformational Dynamics ◽

Md Simulations ◽

Atp Binding ◽

Rna Recognition Motif ◽

Rna Recognition ◽

Nucleic Acid Binding ◽

General Role ◽

Nmr Characterization ◽

Lateral Sclerosis

AbstractTDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

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How do mechanosensitive channels sense membrane tension?

Biochemical Society Transactions ◽

10.1042/bst20160018 ◽

2016 ◽

Vol 44 (4) ◽

pp. 1019-1025 ◽

Cited By ~ 14

Author(s):

Tim Rasmussen

Keyword(s):

Membrane Lipids ◽

Osmotic Shock ◽

Md Simulations ◽

Fatty Acyl ◽

Membrane Bilayer ◽

Cross Sectional ◽

Conducting Path ◽

Lipid Chain ◽

Acyl Chains

Mechanosensitive (MS) channels provide protection against hypo-osmotic shock in bacteria whereas eukaryotic MS channels fulfil a multitude of important functions beside osmoregulation. Interactions with the membrane lipids are responsible for the sensing of mechanical force for most known MS channels. It emerged recently that not only prokaryotic, but also eukaryotic, MS channels are able to directly sense the tension in the membrane bilayer without any additional cofactor. If the membrane is solely viewed as a continuous medium with specific anisotropic physical properties, the sensitivity towards tension changes can be explained as result of the hydrophobic coupling between membrane and transmembrane (TM) regions of the channel. The increased cross-sectional area of the MS channel in the active conformation and elastic deformations of the membrane close to the channel have been described as important factors. However, recent studies suggest that molecular interactions of lipids with the channels could play an important role in mechanosensation. Pockets in between TM helices were identified in the MS channel of small conductance (MscS) and YnaI that are filled with lipids. Less lipids are present in the open state of MscS than the closed according to MD simulations. Thus it was suggested that exclusion of lipid fatty acyl chains from these pockets, as a consequence of increased tension, would trigger gating. Similarly, in the eukaryotic MS channel TRAAK it was found that a lipid chain blocks the conducting path in the closed state. The role of these specific lipid interactions in mechanosensation are highlighted in this review.

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MD Simulations and first principles to evaluate the role of binary Fe–V alloys layer on the radiation resistance in the alpha-iron

Molecular Simulation ◽

10.1080/08927022.2018.1547822 ◽

2018 ◽

Vol 45 (3) ◽

pp. 178-185 ◽

Cited By ~ 2

Author(s):

Meng Zhang ◽

Xinkai Ding ◽

Weixiang Peng ◽

Hongliang Zhang ◽

Bingjie Wu ◽

...

Keyword(s):

First Principles ◽

Radiation Resistance ◽

Md Simulations ◽

Alpha Iron

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The role of BamA in the biogenesis of beta-barrel membrane proteins

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314094212 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C578-C578

Author(s):

Nicholas Noinaj ◽

Adam Kuszak ◽

Curtis Balusek ◽

JC Gumbart ◽

Petra Lukacik ◽

...

Keyword(s):

Membrane Proteins ◽

Outer Membrane ◽

Crystal Structures ◽

Outer Membrane Proteins ◽

Hydrophobic Surface ◽

Md Simulations ◽

Structural Features ◽

Bam Complex ◽

Beta Barrel

Beta-barrel membrane proteins are essential for nutrient import, signaling, motility, and survival. In Gram-negative bacteria, the beta-barrel assembly machinery (BAM) complex is responsible for the biogenesis of beta-barrel outer membrane proteins (OMPs), with homologous complexes found in mitochondria and chloroplasts. Despite their essential roles, exactly how these OMPs are formed remains unknown. The BAM complex consists of a central and essential component called BamA (an OMP itself) and four lipoproteins called BamB-E. While the structure of the lipoproteins have been reported, the structure of full length BamA has been elusive. Recently though, we described the structure of BamA from two species of bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. BamA consists of a large periplasmic domain attached to a 16-strand transmembrane beta-barrel domain. Together, our crystal structures and molecule dynamics (MD) simulations revealed several structural features which gave clues to the mechanism by which BamA catalyzes beta-barrel assembly. The first is that the interior cavity is accessible in one BamA structure and conformationally closed in the other. Second, an exterior rim of the beta-barrel has a distinctly narrowed hydrophobic surface, locally destabilizing the outer membrane. Third, the beta-barrel can undergo lateral opening, suggesting a route from the interior cavity in BamA into the outer membrane. And fourth, a surface exposed exit pore positioned above the lateral opening site which may play a role in the biogenesis of extracellular loops. In this presentation, the crystal structures and MD simulations of BamA will be presented along with our work looking at the role of these four structural features in the role of BamA within the BAM complex.

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Role of tensile elastostatic loading on atomic structure and mechanical properties of Zr55Cu30Ni5Al10 bulk metallic glass

Materials Science and Engineering A ◽

10.1016/j.msea.2019.03.058 ◽

2019 ◽

Vol 753 ◽

pp. 218-223 ◽

Cited By ~ 8

Author(s):

Majid Samavatian ◽

Reza Gholamipour ◽

Ahmad Ali Amadeh ◽

Shamsoddin Mirdamadi

Keyword(s):

Mechanical Properties ◽

Metallic Glass ◽

Bulk Metallic Glass ◽

Atomic Structure

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MiR193a Modulation and Podocyte Phenotype

Cells ◽

10.3390/cells9041004 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1004

Author(s):

Alok Jha ◽

Shourav Saha ◽

Kamesh Ayasolla ◽

Himanshu Vashistha ◽

Ashwani Malhotra ◽

...

Keyword(s):

Transcription Factors ◽

Molecular Markers ◽

Promoter Region ◽

Therapeutic Strategy ◽

Protein Complexes ◽

Md Simulations ◽

Tertiary Structures ◽

Docking Approach ◽

Apolipoprotein L1

Apolipoprotein L1 (APOL1)-miR193a axis has been reported to play a role in the maintenance of podocyte homeostasis. In the present study, we analyzed transcription factors relevant to miR193a in human podocytes and their effects on podocytes’ molecular phenotype. The motif scan of the miR193a gene provided information about transcription factors, including YY1, WT1, Sox2, and VDR-RXR heterodimer, which could potentially bind to the miR193a promoter region to regulate miR193a expression. All structure models of these transcription factors and the tertiary structures of the miR193a promoter region were generated and refined using computational tools. The DNA-protein complexes of the miR193a promoter region and transcription factors were created using a docking approach. To determine the modulatory role of miR193a on APOL1 mRNA, the structural components of APOL1 3’ UTR and miR193a-5p were studied. Molecular Dynamic (MD) simulations validated interactions between miR193a and YY1/WT1/Sox2/VDR/APOL1 3′ UTR region. Undifferentiated podocytes (UPDs) displayed enhanced miR193a, YY1, and Sox2 but attenuated WT1, VDR, and APOL1 expressions, whereas differentiated podocytes (DPDs) exhibited attenuated miR193a, YY1, and Sox2 but increased WT1, VDR, APOL1 expressions. Inhibition of miR193a in UPDs enhanced the expression of APOL1 as well as of podocyte molecular markers; on the other hand, DPD-transfected with miR193a plasmid showed downing of APOL1 as well as podocyte molecular markers suggesting a causal relationship between miR193a and podocyte molecular markers. Silencing of YY1 and Sox2 in UPDs decreased the expression of miR193a but increased the expression of VDR, and CD2AP (a marker of DPDs); in contrast, silencing of WT1 and VDR in DPDs enhanced the expression of miR193a, YY1, and Sox2. Since miR193a-downing by Vitamin D receptor (VDR) agonist not only enhanced the mRNA expression of APOL1 but also of podocyte differentiating markers, suggest that down-regulation of miR193a could be used to enhance the expression of podocyte differentiating markers as a therapeutic strategy.

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