scholarly journals Spider Toxin SNX-482 Gating Modifier Spontaneously Partitions in the Membrane Guided by Electrostatic Interactions

2021 ◽  
Author(s):  
Guido Mellado ◽  
Jose Antonio Garate ◽  
Alan Neely
Keyword(s):  
Aqueous Phase ◽  
Electrostatic Interactions ◽  
Lateral Diffusion ◽  
Critical Factor ◽  
Coarse Grained ◽  
Spider Toxin ◽  
Order Of Magnitude ◽  
Direct Binding ◽  
Dynamics Simulations ◽  
Binding Mechanisms

Spider toxin SNX-482 is a cysteine-rich peptide that interferes with calcium channel activity by binding to voltage-sensing domains of CaV2.3 subtype. Two general binding mechanisms are present in nature: direct binding from the aqueous phase or through lateral diffusion from the membrane, the so-called reduction in dimensionality mechanism. In this work, via coarse-grained and atomistic molecular dynamics simulations, we have systematically studied the spontaneous partitioning of SNX-482 with membranes of different anionic compositions and explored via diffusional analysis both binding mechanisms. Our simulations revealed a conserved protein patch that inserts within the membrane, a preference for binding towards partially negatively charged membranes, and that electrostatics drives membrane binding. Finally, diffusivity calculations showed that the toxin diffusion along the membrane plane is an order of magnitude slower than the aqueous phase suggesting that the critical factor in determin-ing the SNX-482-CaV2.3 binding mechanism is the affinity between the membrane and SNX-482

scholarly journals Tubulin tails and their modifications regulate protein diffusion on microtubules

2020 ◽  
Vol 117 (16) ◽  
pp. 8876-8883 ◽  
Author(s):  
Lavi S. Bigman ◽  
Yaakov Levy
Keyword(s):  
Molecular Mechanism ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Coarse Grained ◽  
Protein Diffusion ◽  
Intrinsically Disordered ◽  
Essential Components ◽  
Regulate Protein ◽  
Dynamics Simulations

Microtubules (MTs) are essential components of the eukaryotic cytoskeleton that serve as “highways” for intracellular trafficking. In addition to the well-known active transport of cargo by motor proteins, many MT-binding proteins seem to adopt diffusional motility as a transportation mechanism. However, because of the limited spatial resolution of current experimental techniques, the detailed mechanism of protein diffusion has not been elucidated. In particular, the precise role of tubulin tails and tail modifications in the diffusion process is unclear. Here, using coarse-grained molecular dynamics simulations validated against atomistic simulations, we explore the molecular mechanism of protein diffusion along MTs. We found that electrostatic interactions play a central role in protein diffusion; the disordered tubulin tails enhance affinity but slow down diffusion, and diffusion occurs in discrete steps. While diffusion along wild-type MT is performed in steps of dimeric tubulin, the removal of the tails results in a step of monomeric tubulin. We found that the energy barrier for diffusion is larger when diffusion on MTs is mediated primarily by the MT tails rather than the MT body. In addition, globular proteins (EB1 and PRC1) diffuse more slowly than an intrinsically disordered protein (Tau) on MTs. Finally, we found that polyglutamylation and polyglycylation of tubulin tails lead to slower protein diffusion along MTs, although polyglycylation leads to faster diffusion across MT protofilaments. Taken together, our results explain experimentally observed data and shed light on the roles played by disordered tubulin tails and tail modifications in the molecular mechanism of protein diffusion along MTs.

scholarly journals Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides

2017 ◽  
Vol 114 (43) ◽  
pp. E8977-E8986 ◽  
Author(s):  
Yosuke Senju ◽  
Maria Kalimeri ◽  
Essi V. Koskela ◽  
Pentti Somerharju ◽  
Hongxia Zhao ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Lipid Bilayer ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Lateral Diffusion ◽  
Lipid Binding ◽  
Actin Binding ◽  
Membrane Interactions ◽  
Dynamics Simulations

The actin cytoskeleton powers membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Membrane phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], regulate the activities of many actin-binding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin, but the underlying molecular mechanisms have remained elusive. Moreover, because of a lack of available methodology, the dynamics of membrane interactions have not been experimentally determined for any ABP. Here, we applied a combination of biochemical assays, photobleaching/activation approaches, and atomistic molecular dynamics simulations to uncover the molecular principles by which ABPs interact with phosphoinositide-rich membranes. We show that, despite using different domains for lipid binding, these proteins associate with membranes through similar multivalent electrostatic interactions, without specific binding pockets or penetration into the lipid bilayer. Strikingly, our experiments reveal that these proteins display enormous differences in the dynamics of membrane interactions and in the ranges of phosphoinositide densities that they sense. Profilin and cofilin display transient, low-affinity interactions with phosphoinositide-rich membranes, whereas F-actin assembly factors Dia2 and N-WASP reside on phosphoinositide-rich membranes for longer periods to perform their functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bind membranes with very high affinity and slow dissociation dynamics. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require high “stimulus-responsive” phosphoinositide density for membrane binding. Moreover, ezrin can limit the lateral diffusion of PI(4,5)P2 along the lipid bilayer. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely fulfill their specific functions in cytoskeletal dynamics.

scholarly journals Ionic transport through a protein nanopore: a Coarse-Grained Molecular Dynamics Study

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nathalie Basdevant ◽  
Delphine Dessaux ◽  
Rosa Ramirez
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayer ◽  
Electric Fields ◽  
Ionic Transport ◽  
Stationary Regime ◽  
Coarse Grained ◽  
Experimental Conditions ◽  
Current Saturation ◽  
Order Of Magnitude ◽  
Dynamics Simulations

Abstract The MARTINI coarse-grained (CG) force field is used to test the ability of CG models to simulate ionic transport through protein nanopores. The ionic conductivity of CG ions in solution was computed and compared with experimental results. Next, we studied the electrostatic behavior of a solvated CG lipid bilayer in salt solution under an external electric field. We showed this approach correctly describes the experimental conditions under a potential bias. Finally, we performed CG molecular dynamics simulations of the ionic transport through a protein nanopore (α-hemolysin) inserted in a lipid bilayer, under different electric fields, for 2–3 microseconds. The resulting I − V curve is qualitatively consistent with experiments, although the computed current is one order of magnitude smaller. Current saturation was observed for potential biases over ±350 mV. We also discuss the time to reach a stationary regime and the role of the protein flexibility in our CG simulations.

scholarly journals Coarse-grained molecular dynamics simulations of nanoplastics interacting with a hydrophobic environment in aqueous solution

RSC Advances ◽  
2021 ◽  
Vol 11 (44) ◽  
pp. 27734-27744
Author(s):  
Lorenz F. Dettmann ◽  
Oliver Kühn ◽  
Ashour A. Ahmed
Keyword(s):  
Carbon Nanotubes ◽  
Molecular Dynamics ◽  
Aqueous Solution ◽  
Water Treatment ◽  
Md Simulations ◽  
Coarse Grained ◽  
Treatment Technologies ◽  
Dynamics Simulations ◽  
Binding Mechanisms ◽  
Soil And Water

The binding mechanisms of nanoplastics (NPs) to carbon nanotubes as hydrophobic environmental systems have been explored by coarse-grained MD simulations. The results could be closely connected to fate of NPs in soil and water treatment technologies.

Structure and energetics of microscopically inhomogeneous nanoplasmas in exploding clusters

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Isidore Last ◽  
Andreas Heidenreich ◽  
Joshua Jortner
Keyword(s):  
Charge Distribution ◽  
Electrostatic Interactions ◽  
Computational Study ◽  
High Energy ◽  
Rich Domain ◽  
Positive Ions ◽  
Ion Energies ◽  
Order Of Magnitude ◽  
Interior Domain ◽  
Dynamics Simulations

AbstractWe present a theoretical-computational study of the formation, structure, composition, energetics, dynamics and expansion of nanoplasmas consisting of high-energy matter on the nanoscale of ions and electrons. Molecular dynamics simulations explored the structure and energetics of hydrogen and neon persistent nanoplasmas formed under the condition of incomplete outer ionization by the laser field. We observed a marked microscopic inhomogeneity of the structure and the charge distribution of exploding nanoplasmas on the nanoscale. This is characterized by a nearly neutral, uniform, interior domain observed for the first time, and a highly positively charged, exterior domain, with these two domains being separated by a transition domain. We established the universality of the general features of the shape of the charge distribution, as well as of the energetics and dynamics of individual ions in expanding persistent nanoplasmas containing different positive ions. The inhomogeneous three-domain shell structure of exploding nanoplasmas exerts major effects on the local ion energies, which are larger by one order of magnitude in the exterior, electron-depleted domain than in the interior, electron-rich domain, with the major contribution to the ion energies originating from electrostatic interactions. The radial structural inhomogeneity of exploding nanoplasmas bears analogy to the inhomogeneous transport regime in expanded and supercritical metals undergoing metal-nonmetal transition.

scholarly journals Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ailing Tong ◽  
John T Petroff ◽  
Fong-Fu Hsu ◽  
Philipp AM Schmidpeter ◽  
Crina M Nimigean ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transmembrane Domain ◽  
Native Mass Spectrometry ◽  
Coarse Grained ◽  
Specific Lipids ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Functional Assays ◽  
Direct Binding ◽  
Dynamics Simulations

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

Expansion and Additional Validation of PKA17: A Fast Real-Time and Web-Based pKa Predictor

2020 ◽  
pp. 1-12
Author(s):  
John P. Cvitkovic ◽  
Connor D. Pauplis ◽  
Phoebe C. Carney ◽  
George A. Kaminski
Keyword(s):  
Metal Ions ◽  
Large Scale ◽  
Transition Metal Ions ◽  
Coarse Grained ◽  
Acidity Constants ◽  
Protein Residues ◽  
Constant Ph ◽  
Computational Speed ◽  
Order Of Magnitude ◽  
Dynamics Simulations

We have further improved and validated PKA17, our fast software for predicting p[Formula: see text] values of protein residues. The methodology employs coarse-grained lattice-based model of proteins. It was previously demonstrated to perform ca. an order of magnitude faster than such successful and widely used frameworks as PROPKA without losing accuracy of the calculations. In this paper, we report the following improvements: (i) We have expanded our training and testing sets of protein residues by 128%, from 442 to 1009 cases; (ii) we have added and parameterized PKA17’s capability to predict acidity constants of cysteine residues that are important in many biomedical applications, including but not limited to binding of such transition metal ions as copper(I) and platinum(II); (iii) we have carried out the comparison of accuracy of predicted Asp and Glu p[Formula: see text] values not only between PKA17 and PROPKA, but also with DelPhiPKa and H[Formula: see text]. The computational speed of PKA17 remains the highest of all the methods used in our studies, and the accuracy of PKA17 is somewhat inferior only to those of such more sophisticated methods as Multi-Conformation Continuum Electrostatic (MCCE) ones. For instance, the average unsigned deviations of predicted p[Formula: see text] values from the experiment for 416 Glu residues were found to be 0.706, 0.766, 0.867, and 0.520[Formula: see text]pH units when obtained with PROPKA, DelPhiPKa, H[Formula: see text], and PKA17, respectively (0.487[Formula: see text]pH units with PKA17 after refitting). The average unsigned errors for cysteine p[Formula: see text] values calculated with PROPKA, DelPhiPKa, H[Formula: see text], and PKA17 were 3.50, 2.06, 3.17, and 1.26[Formula: see text]pH units. PKA17 has also performed well in assessing the cysteine acidity constants of the CXXC motif of CopZ protein involved in binding of copper(I) metal ions. Our results demonstrate that the PKA17 methodology and current parameters are accurate and robust, and its computational speed makes it possible to be employed in large-scale p[Formula: see text] screening calculations and in constant-pH protein dynamics simulations. The resulting PKA17 software has been deployed online at http://kaminski.wpi.edu/PKA17/pka_calc.html.

Layer-by-layer assembly of nanorods on a microsphere via electrostatic interactions

Soft Matter ◽  
2018 ◽  
Vol 14 (22) ◽  
pp. 4541-4550 ◽  
Author(s):  
Liuyang Zhang ◽  
Lu Zhu ◽  
Steven R. Larson ◽  
Yiping Zhao ◽  
Xianqiao Wang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Systematic Study ◽  
Electrostatic Interactions ◽  
Coarse Grained ◽  
Layer By Layer ◽  
Equilibrium Behavior ◽  
Lbl Assembly ◽  
Dynamics Simulations ◽  
Layer Assembly

Combining coarse-grained molecular dynamics simulations and experiments, a systematic study on both the dynamics and equilibrium behavior of the layer-by-layer (LbL) assembly of charged nanorods (NRs) onto a charged microsphere (MS) via electrostatic interactions has been carried out.

Multibody Molecular Dynamics II: Applications and Results

2007 ◽  
Author(s):  
Rudranarayan M. Mukherjee ◽  
Paul Crozier ◽  
Kurt S. Anderson
Keyword(s):  
Molecular Dynamics ◽  
Multibody Dynamics ◽  
Degrees Of Freedom ◽  
Coarse Grained ◽  
Future Research ◽  
Conservation Of Energy ◽  
Order Of Magnitude ◽  
Speed Up ◽  
The Stability ◽  
Dynamics Simulations

This is the second paper in a series of two papers on using multibody dynamics algorithms and methods for coarse grained molecular dynamics simulations. In the previous paper, the theoretical discussions on this topic have been presented. This paper presents results obtained from simulating several biomolecular and bulk materials using multibody dynamics algorithms. The systems studied include water boxes, alkane chains, alanine dipeptide and carboxyl terminal fragments of Calmodulin, Ribosomal, and Rhodopsin proteins. The atomistic representations of these systems include several thousand degrees of freedom and results of several nano-second simulations of these systems are presented. The stability and validity of the simulations are studied through conservation of energy, thermodynamics properties and conformational analysis. In these simulations, a speed up of an order of magnitude is realized for conservative error bounds. A discussion is presented on the open-source software developed to facilitate future research using multibody dynamics with molecular dynamics.

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