Aβ Fibrils Can Act as Aqueous Pores: a Molecular Dynamics Study

AbstractAggregation of Aβ peptides is important in the etiology of Alzheimer’s Disease (AD), an increasingly prevalent neurodegenerative disease. We ran multiple ∼ 300 ns all-atom explicit solvent molecular dynamics (MD) simulations starting from three NMR-based structural models of Aβ(1-40 residues) fibrils having 2-fold (pdb code 2LMN) or 3-fold rotational symmetry (2LMP, and 2M4J). The 2M4J structure is based on an AD brain-seeded fibril whereas 2LMP and 2LMN represent two all-synthetic fibrils. Fibrils are constructed to contain either 6 or an infinite number of layers made using periodic images. The 6 layer fibrils partially unravel over the simulation time, mainly at their ends, while infinitely long fibrils do not. Once formed, the D23-K28 salt bridges are very stable and form within and between chains. Fibrils tend to retain (2LMN and 2LMP) or develop (2M4J) a “stagger” or register shift of β-strands along the fibril axis. The brain-seeded fibril rapidly develops gaps at the sides of the fibril, which allows bidirectional flow of water and ions from the bulk phase in and out the central longitudinal core of the fibril. Similar but less marked changes were also observed for the 2LMP fibrils. The residues defining the gaps largely coincide with those demonstrated to have relatively rapid Hydrogen-Deuterium exchange in solid state NMR studies. These observations suggest that Aβ(1-40 residues) fibrils may act as aqueous pores that might disrupt water and ion fluxes if inserted into a cell membrane.

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Conservation of the conformational dynamics and ligand binding within M49 enzyme family

RSC Advances ◽

10.1039/c7ra13059g ◽

2018 ◽

Vol 8 (24) ◽

pp. 13310-13322 ◽

Cited By ~ 2

Author(s):

Saša Kazazić ◽

Zrinka Karačić ◽

Igor Sabljić ◽

Dejan Agić ◽

Marko Tomin ◽

...

Keyword(s):

Mass Spectrometry ◽

Molecular Dynamics ◽

Ligand Binding ◽

Conformational Dynamics ◽

Md Simulations ◽

Dipeptidyl Peptidase ◽

Deuterium Exchange ◽

Hydrogen Deuterium Exchange ◽

Enzyme Family ◽

Hydrogen Deuterium

The hydrogen deuterium exchange (HDX) mass spectrometry combined with molecular dynamics (MD) simulations was employed to investigate conformational dynamics and ligand binding within the M49 family (dipeptidyl peptidase III family).

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Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics

The Journal of General Physiology ◽

10.1085/jgp.201812235 ◽

2019 ◽

Vol 152 (1) ◽

Cited By ~ 4

Author(s):

Toshiko Yamazawa ◽

Haruo Ogawa ◽

Takashi Murayama ◽

Maki Yamaguchi ◽

Hideto Oyamada ◽

...

Keyword(s):

Molecular Dynamics ◽

Md Simulations ◽

Hek293 Cells ◽

Salt Bridges ◽

Open Probability ◽

Release Channel ◽

Functional Studies ◽

Function Relationship ◽

Interdomain Interactions ◽

Relationship Of

Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation–contraction coupling. Mutations in the RYR1 gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of CICR via RYR1. Thus far, >300 mutations in RYR1 have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure–function relationship of mutant RYR1, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYR1 bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYR1 caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYR1s were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYR1 channel and provide insights into the mechanism of MH caused by the mutations at the NTD.

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RIP-MD: a tool to study residue interaction networks in protein molecular dynamics

PeerJ ◽

10.7717/peerj.5998 ◽

2018 ◽

Vol 6 ◽

pp. e5998 ◽

Cited By ~ 12

Author(s):

Sebastián Contreras-Riquelme ◽

Jose-Antonio Garate ◽

Tomas Perez-Acle ◽

Alberto J.M. Martin

Keyword(s):

Molecular Dynamics ◽

Protein Structures ◽

Md Simulations ◽

Relevant Information ◽

Interaction Networks ◽

Salt Bridges ◽

Residue Interaction ◽

Non Covalent Interactions ◽

Protein Molecular Dynamics ◽

Covalent Interactions

Protein structure is not static; residues undergo conformational rearrangements and, in doing so, create, stabilize or break non-covalent interactions. Molecular dynamics (MD) is a technique used to simulate these movements with atomic resolution. However, given the data-intensive nature of the technique, gathering relevant information from MD simulations is a complex and time consuming process requiring several computational tools to perform these analyses. Among different approaches, the study of residue interaction networks (RINs) has proven to facilitate the study of protein structures. In a RIN, nodes represent amino-acid residues and the connections between them depict non-covalent interactions. Here, we describe residue interaction networks in protein molecular dynamics (RIP-MD), a visual molecular dynamics (VMD) plugin to facilitate the study of RINs using trajectories obtained from MD simulations of proteins. Our software generates RINs from MD trajectory files. The non-covalent interactions defined by RIP-MD include H-bonds, salt bridges, VdWs, cation-π, π–π, Arginine–Arginine, and Coulomb interactions. In addition, RIP-MD also computes interactions based on distances between Cαs and disulfide bridges. The results of the analysis are shown in an user friendly interface. Moreover, the user can take advantage of the VMD visualization capacities, whereby through some effortless steps, it is possible to select and visualize interactions described for a single, several or all residues in a MD trajectory. Network and descriptive table files are also generated, allowing their further study in other specialized platforms. Our method was written in python in a parallelized fashion. This characteristic allows the analysis of large systems impossible to handle otherwise. RIP-MD is available at http://www.dlab.cl/ripmd.

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Molecular Dynamics Simulations of HLA-CW4-Β2M-KIR2DL1 Protein and Homology Modeling of a Complex Associated with Psoriasis Disease (HLA-CW6-Β 2M-KIR2DS1)

10.1101/2021.12.20.473468 ◽

2021 ◽

Author(s):

Mansour H Almatarneh ◽

Ahmad M Alqaisi ◽

Enas K Ibrahim ◽

Ghada G Kayed ◽

Joshua W Hollett

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Complex Structure ◽

3D Structure ◽

Md Simulations ◽

Salt Bridges ◽

Small Peptide ◽

Β2 Microglobulin ◽

Dynamics Simulations ◽

The Right

Molecular dynamics (MD) simulation was used to study the interactions of two immune proteins of HLA-Cw4-β2m-KIR2DL1 complex with small peptide QYDDAVYKL (nine amino acids) in an aqueous solution. This study aims to gain a detailed information about the conformational changes and the dynamics of the complex. The right parameters and force field for performing the MD simulations that was needed to calibrate the complex structure were determined. The non-bonded interactions (Electrostatic and van der Waals contributions), H-bond formation, and salt bridges between the ligand HLA-Cw4 and the receptor KIR2DL1 were estimated using the obtained MD trajectories. The buried surface area due to binding was calculated to get insight into the causes of specificity of receptor to ligand and explains mutations experiment. The study concluded that β2-microglobulin, one part of the complex, is not directly interacting with the peptide at the groove; therefore, it could be neglected from simulation. Our results showed that β2-microglobulin does not have any significant effect on the dynamics of the 3D-structure of the complex. This project will help in understanding to optimize candidate drug design, a small peptide that disrupts the interaction, for the optimal biological effect.

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Abstract 16069: Molecular Dynamics Simulations Reveal the Functional Impact of Pathogenic Variants in the LDL Receptor LA 4-6 Repeats

Circulation ◽

10.1161/circ.142.suppl_3.16069 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jose James ◽

Iftikhar J Kullo

Keyword(s):

Molecular Dynamics ◽

Long Range ◽

Conformational Dynamics ◽

Md Simulations ◽

Global Changes ◽

Salt Bridges ◽

Stable Conformation ◽

Pathogenic Variants ◽

Ldl Binding ◽

The Impact

Introduction: Functional annotation of rare variants is key to the implementation of genomic medicine. We used molecular dynamics (MD) simulations to assess functional consequences of putative pathogenic variants (PVs) in the low-density lipoprotein receptor gene ( LDLR ). LDLR has a multidomain structure with seven LA repeats and local interactions between these repeats influence ligand binding. However, binding and recycling of the receptor-ligand complex require global changes in conformation. Using MD, we investigated the effects of PVs on long-range dynamics and LDL binding. Methods: An LA 4-6 repeat structure was created from a crystal structure of the extracellular domain (PDB: 1N7D). Structures were solvated with a water box containing TIP3P water molecules and simulated using the AMBER software package with the ff14SB forcefield. The wild type (WT) structure was first relaxed using MD; and subsequently PVs D245Y, F181Y and F181G were modeled. Dynamics were simulated for approximately one microsecond. Values for LDL binding for each PV were obtained from a prior study which used a radioisotope uptake assay. Results: WT domains demonstrated a stable conformation based on root mean square deviation. PVs disrupted the normal distribution in all domains significantly (p < 0.0001), broadening it and introducing multiple peaks. Projection along the top principal components (PCs) showed global destabilization with all PVs. The variant with the greatest impact on LDL binding, F181G, adopted a distinct alternate conformation. Comparison between PV and WT subspaces from PCA correlated with LDL binding (R 2 = 0.99, exponential regression). Structural analysis revealed that the LA5 calcium cage is involved in inter-domain salt bridges, which are disrupted in simulations of PVs. Conclusion: MD simulation of LA4-6 repeats in LDLR suggests PVs alter long-range conformational dynamics, and that such dynamics correlate with LDL binding. The impact of PVs on conformational dynamics and binding may be through disruption of interdomain salt bridges that are mediated by the acidic calcium cage. This study demonstrates the potential utility of MD simulations to functionally characterize LDLR variants.

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Three-dimensional structure of Megabalanus rosa Cement Protein 20 revealed by multi-dimensional NMR and molecular dynamics simulations

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0198 ◽

2019 ◽

Vol 374 (1784) ◽

pp. 20190198 ◽

Cited By ~ 2

Author(s):

Harini Mohanram ◽

Akshita Kumar ◽

Chandra S. Verma ◽

Konstantin Pervushin ◽

Ali Miserez

Keyword(s):

Molecular Dynamics ◽

Disulfide Bonds ◽

Molecular Mechanisms ◽

Tertiary Structure ◽

Three Dimensional ◽

Md Simulations ◽

Dimensional Structure ◽

Nmr Studies ◽

Dynamics Simulations ◽

Cement Protein

Barnacles employ a protein-based cement to firmly attach to immersed substrates. The cement proteins (CPs) have previously been identified and sequenced. However, the molecular mechanisms of adhesion are not well understood, in particular, because the three-dimensional molecular structure of CPs remained unknown to date. Here, we conducted multi-dimensional nuclear magnetic resonance (NMR) studies and molecular dynamics (MD) simulations of recombinant Megabalanus rosa Cement Protein 20 ( r MrCP20). Our NMR results show that r MrCP20 contains three main folded domain regions intervened by two dynamic loops, resulting in multiple protein conformations that exist in equilibrium. We found that 12 out of 32 Cys in the sequence engage in disulfide bonds that stabilize the β -sheet domains owing to their placement at the extremities of β -strands. Another feature unveiled by NMR is the location of basic residues in turn regions that are exposed to the solvent, playing an important role for intermolecular contact with negatively charged surfaces. MD simulations highlight a highly stable and conserved β -motif ( β 7- β 8), which may function as nuclei for amyloid-like nanofibrils previously observed in the cured adhesive cement. To the best of our knowledge, this is the first report describing the tertiary structure of an extracellular biological adhesive protein at the molecular level. This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.

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Computational Simulations of Li Ion Conduction in (Li,La)TiO3

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.320.275 ◽

2006 ◽

Vol 320 ◽

pp. 275-278 ◽

Cited By ~ 3

Author(s):

Toyoki Okumura ◽

Ayumi Dodomi ◽

Morihiro Saito ◽

Jun Kuwano

Keyword(s):

Molecular Dynamics ◽

Neutron Diffraction ◽

First Principles ◽

Pair Correlation ◽

Md Simulations ◽

Computational Simulations ◽

Nmr Studies ◽

Local Environments ◽

Li Ion ◽

A Site

The locations and local environments of the Li ions in La0.56Li0.33TiO3 have been investigated by classical molecular dynamics (MD) simulations and first-principles (FP) calculations. The pair correlation functions of Li-O and Li-Ti indicate that the Li ions are located somewhat broadly mainly in the vicinity of the midpoint between the center of the A-site and the center of the bottleneck formed by four O2-. This is consistent well with that suggested from previous neutron diffraction and 6Li-NMR studies. The FP calculations suggest a different location of the Li ion in the vicinity of the midpoint between the centers of two adjcent bottlenecks; however it coincides with one of the locations shown by the trajectories simulated with the MD calculations.

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Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling

International Journal of Molecular Sciences ◽

10.3390/ijms22010270 ◽

2020 ◽

Vol 22 (1) ◽

pp. 270

Author(s):

Hisham M. Dokainish ◽

Yuji Sugita

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Md Simulations ◽

Conformational Sampling ◽

Salt Bridges ◽

Multidomain Proteins ◽

Charged Residues ◽

Ligand Interactions ◽

Moving Domains ◽

Domain Motions

Conformational transitions in multidomain proteins are essential for biological functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. Unfortunately, the atomically detailed mechanisms for such open-closed conformational changes are difficult to be accessed experimentally as well as computationally. To simulate the transitions using atomistic molecular dynamics (MD) simulations, efficient conformational sampling algorithms are required. In this work, we propose a new approach based on generalized replica-exchange with solute tempering (gREST) for exploring the open-closed conformational changes in multidomain proteins. Wherein, selected surface charged residues in a target protein are defined as the solute region in gREST simulation and the solute temperatures are different in replicas and exchanged between them to enhance the domain motions. This approach is called gREST selected surface charged residues (gREST_SSCR) and is applied to the Apo and Holo states of ribose binding protein (RBP) in solution. The conformational spaces sampled with gREST_SSCR are much wider than those with the conventional MD, sampling open-closed conformational changes while maintaining RBP domains’ stability. The free-energy landscapes of RBP in the Apo and Holo states are drawn along with twist and hinge angles of the two moving domains. The inter-domain salt-bridges that are not observed in the experimental structures are also important in the intermediate states during the conformational changes.

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Development of transferable coarse-grained models of amino acids

Molecular Systems Design & Engineering ◽

10.1039/c9me00173e ◽

2020 ◽

Vol 5 (3) ◽

pp. 675-685 ◽

Cited By ~ 3

Author(s):

Olivia Conway ◽

Yaxin An ◽

Karteek K. Bejagam ◽

Sanket A. Deshmukh

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Md Simulations ◽

Peptide Amphiphiles ◽

Coarse Grained ◽

Explicit Solvent

We have developed transferable coarse-grained (CG) models of the twenty standard amino acids, which can be used to perform molecular dynamics (MD) simulations of peptide amphiphiles (PAs) in the presence of explicit solvent.

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