MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations

Gowers, Richard; Linke, Max; Barnoud, Jonathan; Reddy, Tyler; Melo, Manuel N.; Seyler, Sean L.; Domański, Jan; Dotson, David; Buchoux, Sébastien; Kenney, Ian M.; Beckstein, Oliver

doi:10.25080/majora-629e541a-00e

Cited by 1,290 publications

(1,243 citation statements)

References 33 publications

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“…ATP hydrolysis was performed as previously described in which a transformation from ATP to ADP and phosphate is performed. In order to select conformations suited for ATP hydrolysis, several analyses were carried using MDAnalysis . The system Hamiltonian was coupled to a lambda parameter that varies from 0 to 1.…”

Section: Methodsmentioning

confidence: 99%

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F508del disturbs the dynamics of the nucleotide binding domains of CFTR before and after ATP hydrolysis

et al. 2019

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The cystic fibrosis transmembrane conductance regulator (CFTR) channel is an ion channel responsible for chloride transport in epithelia and it belongs to the class of ABC transporters. The deletion of phenylalanine 508 (F508del) in CFTR is the most common mutation responsible for cystic fibrosis. Little is known about the effect of the mutation in the isolated nucleotide binding domains (NBDs), on dimer dynamics, ATP hydrolysis and even on nucleotide binding. Using molecular dynamics simulations of the human CFTR NBD dimer, we showed that F508del increases, in the prehydrolysis state, the inter‐motif distance in both ATP binding sites (ABP) when ATP is bound. Additionally, a decrease in the number of catalytically competent conformations was observed in the presence of F508del. We used the subtraction technique to study the first 300 ps after ATP hydrolysis in the catalytic competent site and found that the F508del dimer evidences lower conformational changes than the wild type. Using longer simulation times, the magnitude of the conformational changes in both forms increases. Nonetheless, the F508del dimer shows lower C‐α RMS values in comparison to the wild‐type, on the F508del loop, on the residues surrounding the catalytic site and the portion of NBD2 adjacent to ABP1. These results provide evidence that F508del interferes with the NBD dynamics before and after ATP hydrolysis. These findings shed a new light on the effect of F508del on NBD dynamics and reveal a novel mechanism for the influence of F508del on CFTR.

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Section: Methodsmentioning

confidence: 99%

“…The C‐α RMS between the existing NBD1 structures and the NBD1 of our model was calculated using MDAnalysis …”

Section: Methodsmentioning

confidence: 99%

F508del disturbs the dynamics of the nucleotide binding domains of CFTR before and after ATP hydrolysis

et al. 2019

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“…SciPy,[76,77] Cython,[78] Matplotlib,[79] VMD v1.9.3,[80] MDAnalysis v.0.16.2,[81,82] MDtraj v1.9.0[83] were employed for analyses. SHIFTX2 was used to compute the full set of chemical shifts of C99 in each frame for thermodynamic conditions of 7.4 pH and 310 K temperature.…”

Section: Methodsmentioning

confidence: 99%

Structure of APP-C991–99 and implications for role of extra-membrane domains in function and oligomerization

Pantelopulos

Straub

Thirumalai

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The 99 amino acid C-terminal fragment of Amyloid Precursor Protein APP-C99 (C99) is cleaved by γ-secretase to form Aβ peptide, which plays a critical role in the etiology of Alzheimer's Disease (AD). The structure of C99 consists of a single transmembrane domain flanked by intra and intercellular domains. While the structure of the transmembrane domain has been well characterized, little is known about the structure of the flanking domains and their role in C99 processing by γ-secretase. To gain insight into the structure of full-length C99, REMD simulations were performed for monomeric C99 in model membranes of varying thickness. We find equilibrium ensembles of C99 from simulation agree with experimentally-inferred residue insertion depths and protein backbone chemical shifts. In thin membranes, the transmembrane domain structure is correlated with extra-membrane structural states and the extra-membrane domain structural states become less correlated to each other. Mean and variance of the transmembrane and GG hinge angles are found to increase with thinning membrane. The N-terminus of C99 forms β-strands that may seed aggregation of Aβ on the membrane surface, promoting amyloid formation. In thicker membranes the N-terminus forms α-helices that interact with the nicastrin domain of γ-secretase. The C-terminus of C99 becomes more α-helical as the membrane thickens, forming structures that may be suitable for binding by cytoplasmic proteins, while C-terminal residues essential to cytotoxic function become α-helical as the membrane thins. The heterogeneous but discrete extra-membrane domain states analyzed here open the path to new investigations of the role of C99 structure and membrane in amyloidogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

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“…; Gowers et al . ) and also used the ‘sasa’ tool included with GROMACS 2016 (Hess et al . ; Abraham et al .…”

Section: Methodsmentioning

confidence: 99%

“…The axial angle of residue F99 was calculated as described in Yeung et al (2018). Analyses were performed using MDAnalysis 0.18.0 (Michaud-Agrawal et al 2011;Gowers et al 2016) and also used the 'sasa' tool included with GROMACS 2016 (Hess et al 2008;Abraham et al 2015). Structural figures were prepared using PyMOL 1.8.2.1.…”

Section: Human Orai1 Model Generation and Molecular Dynamics Simulationsmentioning

confidence: 99%

ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain

Bulla

Gyimesi

Kim

et al. 2018

The Journal of Physiology

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Key points Gain‐of‐function mutations in the highly selective Ca2+ channel ORAI1 cause tubular aggregate myopathy (TAM) characterized by muscular pain, weakness and cramping. TAM‐associated mutations in ORAI1 first and third transmembrane domain facilitate channel opening by STIM1, causing constitutive Ca2+ influx and increasing the currents evoked by Ca2+ store depletion. Mutation V107M additionally decreases the channel selectivity for Ca2+ ions and its inhibition by acidic pH, while mutation T184M does not alter the channel sensitivity to pH or to reactive oxygen species. The ORAI blocker GSK‐7975A prevents the constitutive activity of TAM‐associated channels and might be used in therapy for patients suffering from TAM. Abstract Skeletal muscle differentiation relies on store‐operated Ca2+ entry (SOCE) mediated by STIM proteins linking the depletion of endoplasmic/sarcoplasmic reticulum Ca2+ stores to the activation of membrane Ca2+‐permeable ORAI channels. Gain‐of‐function mutations in STIM1 or ORAI1 isoforms cause tubular aggregate myopathy (TAM), a skeletal muscle disorder with muscular pain, weakness and cramping. Here, we characterize two overactive ORAI1 mutants from patients with TAM: V107M and T184M, located in the first and third transmembrane domain of the channel. When ectopically expressed in HEK‐293T cells or human primary myoblasts, the mutated channels increased basal and store‐operated Ca2+ entry. The constitutive activity of V107M, L138F, T184M and P245L mutants was prevented by low concentrations of GSK‐7975A while the G98S mutant was resistant to inhibition. Electrophysiological recordings confirmed ORAI1‐V107M constitutive activity and revealed larger STIM1‐gated V107M‐ and T184M‐mediated currents with conserved fast and slow Ca2+‐dependent inactivation. Mutation V107M altered the channel selectivity for Ca2+ ions and conferred resistance to acidic inhibition. Ca2+ imaging and molecular dynamics simulations showed a preserved sensitivity of T184M to the negative regulation by reactive oxygen species. Both mutants were able to mediate SOCE in Stim1−/−/Stim2−/− mouse embryonic fibroblasts expressing the binding‐deficient STIM1‐F394H mutant, indicating a higher sensitivity for STIM1‐mediated gating, with ORAI1‐T184M gain‐of‐function being strictly dependent on STIM1. These findings provide new insights into the permeation and regulatory properties of ORAI1 mutants that might translate into therapies against diseases with gain‐of‐function mutations in ORAI1.

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MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations

Cited by 1,290 publications

References 33 publications

F508del disturbs the dynamics of the nucleotide binding domains of CFTR before and after ATP hydrolysis

F508del disturbs the dynamics of the nucleotide binding domains of CFTR before and after ATP hydrolysis

Structure of APP-C991–99 and implications for role of extra-membrane domains in function and oligomerization

ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain

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