Molecular dynamics of the cryo-EM CFTR structure

Tordai, Hedvig; Leveles, Ibolya; Hegedüs, Tamás

doi:10.1016/j.bbrc.2017.07.165

Cited by 14 publications

(13 citation statements)

References 42 publications

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“…To overcome the limitations of static structures, several molecular dynamics studies have been performed. Tordai et al performed simulations with the apo zebrafish CFTR structure, which was determined in the absence of ATP and exhibited separated NBDs [21]. In this study, it was suggested that this conformation is not highly populated under physiological condition, since closure of the NBDs could be observed even in short simulations.…”

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confidence: 76%

Discovering the chloride pathway in the CFTR channel

Farkas

Tordai

Padányi

et al. 2019

Cell. Mol. Life Sci.

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Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

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confidence: 76%

Discovering the chloride pathway in the CFTR channel

Farkas

Tordai

Padányi

et al. 2019

Cell. Mol. Life Sci.

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“…We have recently investigated the dynamics of the inward-facing CFTR cryo-EM structure and noticed the closure of the nucleotide binding domains ( Fig. 3 a in [ 44 ]). As the measures we have calculated were not sufficient to fully understand the movements of the protein in detail, we analyzed the trajectories employing conftors.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, at the intramolecular interaction site of the L0/Lasso motive preceding the first transmembrane domain in ABCC proteins, such as ABCC1/MRP1 (Fig. S7) and ABCC7/CFTR [ 44 ] the positive ring breaks with a hydrophobic spot. The functionally important amphipathic α-helix of the L0/Lasso motif binds to this patch as observed in several cryo-EM structures.…”

Section: Resultsmentioning

confidence: 99%

“…Coarse-grained simulations were performed with structures of PDB entries 2HYD, 3Qf4, 4KSB, 5UAK, 5TSI, 5UJ9, and 4PL0 using GROMACS with the MARTINI force field (elnedyn22) [ 42 , 43 ]. Trajectories of all-atom simulations have been obtained using GROMACS as described earlier [ 44 ]. More details on simulation parameters are in the supplementary material.…”

Section: Methodsmentioning

confidence: 99%

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Quantitative comparison of ABC membrane protein type I exporter structures in a standardized way

Csizmadia

Farkas

Spagina

et al. 2018

Computational and Structural Biotechnology Journal

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SummaryAn increasing number of ABC membrane protein structures are determined by cryo-electron microscopy and X-ray crystallography, consequently identifying differences between their conformations has become an arising issue. Therefore, we propose to define standardized measures for ABC Type I exporter structure characterization. We set conformational vectors, conftors, which describe the relative orientation of domains and can highlight structural differences. In addition, continuum electrostatics calculations were performed to characterize the energetics of membrane insertion illuminating functionally crucial regions. In summary, the proposed metrics contribute to deeper understanding of ABC membrane proteins' structural features, structure validation, and analysis of movements observed in a molecular dynamics trajectory. Moreover, the concept of standardized metrics can be applied not only to ABC membrane protein structures (http://conftors.hegelab.org).

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“…As a result, ideally, a resolution of 3 Å or better is necessary for structure based predictions and drug design. Structures at lower resolution can still be useful; molecular dynamics and other computational methods can be used to fit and minimize the structure and assign the most probable loop conformations and residue rotamers (Trabuco et al, 2008) (Zhao et al, 2013) (Arenz et al, 2016) (Tordai et al, 2017), as well as build de novo structures (Das and Baker, 2008) or identify the position of chemically relevant waters (Wang et al, 2011) (Jukič et al, 2017). The combination of low resolution experimental structures and modeling can become a powerful tool for SBDD, particularly if orthogonal validation methods and checks are available.…”

Section: Introductionmentioning

confidence: 99%