Sequential activation of STIM1 links Ca2+ with luminal domain unfolding

2019 ◽  
Vol 12 (608) ◽  
pp. eaax3194 ◽  
Author(s):  
Romana Schober ◽  
Daniel Bonhenry ◽  
Victoria Lunz ◽  
Jinhui Zhu ◽  
Adela Krizova ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Level ◽  
Point Mutations ◽  
Md Simulations ◽  
Sam Domain ◽  
Store Depletion ◽  
Ef Hand ◽  
Sequential Activation ◽  
Ef Hands ◽  
Hydrophobic Cleft

The stromal interaction molecule 1 (STIM1) has two important functions, Ca2+ sensing within the endoplasmic reticulum and activation of the store-operated Ca2+ channel Orai1, enabling plasma-membrane Ca2+ influx. We combined molecular dynamics (MD) simulations with live-cell recordings and determined the sequential Ca2+-dependent conformations of the luminal STIM1 domain upon activation. Furthermore, we identified the residues within the canonical and noncanonical EF-hand domains that can bind to multiple Ca2+ ions. In MD simulations, a single Ca2+ ion was sufficient to stabilize the luminal STIM1 complex. Ca2+ store depletion destabilized the two EF hands, triggering disassembly of the hydrophobic cleft that they form together with the stable SAM domain. Point mutations associated with tubular aggregate myopathy or cancer that targeted the canonical EF hand, and the hydrophobic cleft yielded constitutively clustered STIM1, which was associated with activation of Ca2+ entry through Orai1 channels. On the basis of our results, we present a model of STIM1 Ca2+ binding and refine the currently known initial steps of STIM1 activation on a molecular level.

On the interface of organic aerosols: molecular level understanding of surface melting, mixing and water adsorption/desorption dynamics

2021 ◽  
Author(s):  
Josip Lovrić ◽  
Xiangrui Kong ◽  
Sofia M. Johansson ◽  
Erik S. Thomson ◽  
Jan B. C. Pettersson
Keyword(s):  
Physical Chemistry ◽  
Molecular Dynamics ◽  
Melting Point ◽  
Molecular Beam ◽  
Molecular Level ◽  
Organic Aerosols ◽  
Md Simulations ◽  
Valeric Acid ◽  
Good Representative ◽  
Hydrophilic Character

<p>The detailed description of organic aerosols surfaces in the atmosphere remains an open issue, which limits our ability to understand and predict environmental change. Important research questions concern the hydrophobic/hydrophilic character of fresh and aged aerosols and the related influence on water uptake in solid, liquid as well in intermediate state.  Also, surface characterization remains big challenge but we find it reachable by conjunction of Molecular Dynamics (MD) simulations and the environmental molecular beam (EMB) experimental method.  A  picture of the detailed molecular-level behavior of water molecules on organic surfaces is beginning to rise based on detailed experimental and theoretical studies; one example is a recent study that investigates water interactions with solid and liquid n-butanol near the melting point [1], another example focus on interaction of water with solid nopinone [2]. From the other side, in order to characterize surface properties during and before melting we employ MD simulations of n-butanol, nopinone and valeric acid. Nopinone (C<sub>9</sub>H<sub>14</sub>O) is a reaction product formed during oxidation of β-pinene and has been found in both the gas and particle phases of atmospheric aerosol. n-butanol (C<sub>4</sub>H<sub>9</sub>OH) is primary alcohol, naturally occurs scarcely and here serves as good representative for alcohols. In the same way valeric acid (CH<sub>3</sub>(CH<sub>2</sub>)<sub>3</sub>COOH) serves as a good representative for a family of carboxylic acids. Valeric acid is, as n-butanol, straight-chain molecule. We show that a classical force field for organic material is able to model crystal and liquid structures. The surface properties near the melting point of the condensed phase are reported, and the hydrophobic and hydrophilic character of the surface layer is discussed.  Overall surface melting dynamic is presented and quantified in the terms of structural and geometrical properties. Mixing of a methanol with the solid nopinone surface is examined and hereby presented.</p><p><strong>References</strong></p><p>[1] Johansson, S. M., Lovrić, J., Kong, X., Thomson, E. S., Papagiannakopoulos, P., Briquez, S., Toubin, C, Pettersson, J. B. C. (2019). Understanding water interactions with organic surfaces: environmental molecular beam and molecular dynamics studies of the water–butanol system. Physical Chemistry Chemical Physics. https://doi.org/10.1039/C8CP04151B   </p><p>[2] Johansson, S. M., Lovrić, J., Kong, X., Thomson, E. S., Hallquist, M., & Pettersson, J. B. C. (2020). Experimental and Computational Study of Molecular Water Interactions with Condensed Nopinone Surfaces Under Atmospherically Relevant Conditions. The Journal of Physical Chemistry A, acs.jpca.9b10970. https://doi.org/10.1021/acs.jpca.9b10970</p><p>Keywords: Molecular Dynamics, organic crystal, organic aerosols, water uptake, surface procesess, molecular level</p>

scholarly journals Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 904 ◽  
Author(s):  
Arnold Amusengeri ◽  
Rolland Bantar Tata ◽  
Özlem Tastan Bishop
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Network Analysis ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Point Mutations ◽  
Md Simulations ◽  
Conformational Plasticity ◽  
New Perspective ◽  
The Impact

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

scholarly journals Structural elements within the methylation loop (residues 112–117) and EF hands III and IV of calmodulin are required for Lys115 trimethylation

1999 ◽  
Vol 340 (2) ◽  
pp. 417-424 ◽  
Author(s):  
Jennifer A. COBB ◽  
Chang-Hoon HAN ◽  
David M. WILLS ◽  
Daniel M. ROBERTS
Keyword(s):  
Single Point ◽  
Point Mutations ◽  
Site Directed Mutagenesis ◽  
Structural Elements ◽  
Nad Kinase ◽  
Wild Type ◽  
Loop Sequence ◽  
Ef Hand ◽  
Single Point Mutations ◽  
Ef Hands

Calmodulin is trimethylated by a specific methyltransferase on Lys115, a residue located in a six amino acid loop (LGEKLT) between EF hands III and IV. To investigate the structural requirements for methylation, domain exchange mutants as well as single point mutations of conserved methylation loop residues (E114A, Glu114 → Ala; L116T, Leu116 → Thr) were generated. E114A and L116T activated cyclic nucleotide phosphodiesterase (PDE) and NAD+ kinase (NADK) similar to wild-type calmodulin, but lost their ability to be methylated. Domain exchange mutants in which EF hand III or IV was replaced by EF hand I or II respectively (CaM1214 and CaM1232 respectively) showed a modest effect on PDE and NADK activation (50 to 100% of wild-type), but calmodulin methylation was abolished. A third domain exchange mutant, CaMEKL, has the methylation loop sequence placed at a symmetrical position between EF hands I and II in the N-terminal lobe [residues QNP(41-43) replaced by EKL]. CaMEKL activated PDE normally, but did not activate NADK. However, CaMEKL retained the ability to bind to NADK and inhibited activation by wild-type calmodulin. Site-directed mutagenesis of single residues showed that Gln41 and Pro43 substitutions had the strongest effect on NADK activation. Additionally, CaMEKL was not methylated, suggesting that the introduction of the methylation loop between EF hands I and II is not adequate for methyltransferase recognition. Overall the data indicate that residues in the methylation loop are essential but not sufficient for methyltransferase recognition, and that additional residues unique to EF hands III and IV are required. Secondly, the QNP sequence in the loop between EF hands I and II is necessary for NADK activation.

scholarly journals Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes

2020 ◽  
Vol 21 (12) ◽  
pp. 4410 ◽  
Author(s):  
Matthias Sallinger ◽  
Adéla Tiffner ◽  
Tony Schmidt ◽  
Daniel Bonhenry ◽  
Linda Waldherr ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Md Simulations ◽  
2D Nmr ◽  
Enhanced Production ◽  
Store Depletion ◽  
Ef Hand ◽  
Structure Simulation ◽  
Transcription Factor Eb ◽  
Partial Unfolding ◽  
Ca2 Channels

Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca2+ sensor protein that induces permeation of Orai Ca2+ channels upon endoplasmic reticulum Ca2+-store depletion. A drop in luminal Ca2+ causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca2+ depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure. Simulation- and structure-based results showed unfolding of two α-helices in the canonical and in the non-canonical EF-hand. Further, we structurally and functionally evaluated mutations in the non-canonical EF-hand that have been shown to cause tubular aggregate myopathy. We found these mutations to cause full constitutive activation of Ca2+-release-activated Ca2+ currents (ICRAC) and to promote autophagic processes. Specifically, heterologously expressed STIM1 mutations in the non-canonical EF-hand promoted translocation of the autophagy transcription factors microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB) into the nucleus. These STIM1 mutations additionally stimulated an enhanced production of autophagosomes. In summary, mutations in STIM1 that cause structural unfolding promoted Ca2+ down-stream activation of autophagic processes.

Molecular-Level Modeling of Interfacial Phenomena: Use of Molecular Dynamics Simulations in Tandem With Statistical Thermodynamics Models

2007 ◽  
Author(s):  
Van P. Carey
Keyword(s):  
Molecular Dynamics ◽  
Md Simulation ◽  
Molecular Level ◽  
Md Simulations ◽  
Statistical Thermodynamics ◽  
Liquid Films ◽  
Thin Liquid Films ◽  
Interfacial Phenomena ◽  
Bulk Liquid ◽  
Interfacial Region

Nanoscale aspects of interfacial phenomena can be critically import in convective vaporization and condensation in nanochannels or microchannels. Molecular dynamics (MD) simulations have been extensively used to model and explore the physics of interfacial phenomena at the molecular level. Efforts to improve MD simulations have often focused on development of more physically realistic interaction potentials used to model intermolecular force interactions, or on development of more efficient computing strategies. An important, and often overlooked aspect of MD simulations is the role that theoretical models from statistical thermodynamics can play in MD simulations. This paper argues that use of alternate statistical thermodynamics models, and unconventional strategies for using them, can be effective ways of enhancing MD simulations. The advantages of these types of approaches are explored in the context of three recent MD simulation studies of interfacial region thermophysics that have made use of statistical thermodynamics theory in novel ways. Examples considered include studies of the interfacial region between bulk liquid and vapor phases, thin liquid films on solid surfaces, and stability free thin liquid films. These examples illustrate ways that MD simulations can be combined with other models to enhance computational efficiency or extract more information from the MD simulation results. Successful strategies for implementing these types of scheme are examined, and their general applicability is assessed.

scholarly journals Effects of knot tightness at the molecular level

2019 ◽  
Vol 116 (7) ◽  
pp. 2452-2457 ◽  
Author(s):  
Liang Zhang ◽  
Jean-François Lemonnier ◽  
Angela Acocella ◽  
Matteo Calvaresi ◽  
Francesco Zerbetto ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Dynamics ◽  
Closed Loop ◽  
Molecular Level ◽  
Md Simulations ◽  
Collision Induced Dissociation ◽  
Absorption Properties ◽  
Covalent Bonds ◽  
H Nmr ◽  
Nmr Diffusion

Three 819 knots in closed-loop strands of different lengths (∼20, 23, and 26 nm) were used to experimentally assess the consequences of knot tightness at the molecular level. Through the use of 1H NMR, diffusion-ordered spectroscopy (DOSY), circular dichroism (CD), collision-induced dissociation mass spectrometry (CID-MS) and molecular dynamics (MD) simulations on the different-sized knots, we find that the structure, dynamics, and reactivity of the molecular chains are dramatically affected by the tightness of the knotting. The tautness of entanglement causes differences in conformation, enhances the expression of topological chirality, weakens covalent bonds, inhibits decomplexation events, and changes absorption properties. Understanding the effects of tightening nanoscale knots may usefully inform the design of knotted and entangled molecular materials.

Nano-Tribology of a Polytetrafluoroethylene Transfer Films Using Molecular Dynamics Simulation and Microtribometry

2005 ◽  
Author(s):  
Inkook Jang ◽  
Pamela L. Dickrell ◽  
David L. Burris ◽  
W. Gregory Sawyer ◽  
Simon R. Phillpot ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Polymer Nanocomposites ◽  
Solid Lubricant ◽  
Molecular Level ◽  
Md Simulations ◽  
Polymer Materials ◽  
Dynamics Simulation ◽  
Frictional Behavior ◽  
Transfer Films

Polytetrafluoroethylene (PTFE) is a well known solid lubricant and polymer nanocomposites based on PTFE are considered to be promising materials for tribological applications in space. Like other polymer materials, many properties of PTFE depend on morphology. In this study, molecular dynamics (MD) simulations are performed to examine the effect of chain configuration on the frictional behavior of PTFE at the molecular level and compared to microtribological studies on aligned transfer films of PTFE.

Efficient Treatment of Fixed and Induced Dipolar Interactions

2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Lagrangian Formalism ◽  
Dipolar Interactions ◽  
Time Step ◽  
Efficient Treatment ◽  
Particle Mesh Ewald ◽  
Fixed Charges ◽  
Self Consistency ◽  
Induced Dipoles

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.

Split the Charge Difference in Two! a Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations

2020 ◽  
Author(s):  
Matías R. Machado ◽  
Sergio Pantano
Keyword(s):  
Molecular Dynamics ◽  
Ionic Strength ◽  
Molecular Simulations ◽  
Md Simulations ◽  
Good Practices ◽  
Rule Of Thumb ◽  
Ionic Concentrations

<p> Despite the relevance of properly setting ionic concentrations in Molecular Dynamics (MD) simulations, methods or practical rules to set ionic strength are scarce and rarely documented. Based on a recently proposed thermodynamics method we provide an accurate rule of thumb to define the electrolytic content in simulation boxes. Extending the use of good practices in setting up MD systems is promptly needed to ensure reproducibility and consistency in molecular simulations.</p>

Assessing the Antimalarial Potentials of Phytochemicals: Virtual Screening, Molecular Dynamics and In-Vitro Investigations

2019 ◽  
Vol 16 (3) ◽  
pp. 291-300
Author(s):  
Saumya K. Patel ◽  
Mohd Athar ◽  
Prakash C. Jha ◽  
Vijay M. Khedkar ◽  
Yogesh Jasrai ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Integrity ◽  
Md Simulations ◽  
Tylophora Indica ◽  
Multidrug Resistance Protein 1 ◽  
Receptor Complexes ◽  
Resistance Protein ◽  
Dynamics Simulations ◽  
Stable Trajectory

Background: Combined in-silico and in-vitro approaches were adopted to investigate the antiplasmodial activity of Catharanthus roseus and Tylophora indica plant extracts as well as their isolated components (vinblastine, vincristine and tylophorine). </P><P> Methods: We employed molecular docking to prioritize phytochemicals from a library of 26 compounds against Plasmodium falciparum multidrug-resistance protein 1 (PfMDR1). Furthermore, Molecular Dynamics (MD) simulations were performed for a duration of 10 ns to estimate the dynamical structural integrity of ligand-receptor complexes. </P><P> Results: The retrieved bioactive compounds viz. tylophorine, vinblastin and vincristine were found to exhibit significant interacting behaviour; as validated by in-vitro studies on chloroquine sensitive (3D7) as well as chloroquine resistant (RKL9) strain. Moreover, they also displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations. </P><P> Conclusion: We anticipate that the retrieved phytochemicals can serve as the potential hits and presented findings would be helpful for the designing of malarial therapeutics.

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