The Power Stroke Driven by ATP Binding in CFTR As Studied by Molecular Dynamics Simulations

Furukawa-Hagiya, Tomoka; Furuta, Tadaomi; Chiba, Shuntaro; Saito, Yoshiro; Sakurai, Minoru

doi:10.1021/jp308315w

Cited by 31 publications

(55 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The outward facing models 14,[17][18][19][20][21][22][23] were based primarily on the Sav1866 structure as a template, 24 although recently the newly solved ABC transporter structure McjD 25 has been used to model this state. 26 Inward facing models were based either on the bacterial MsbA 27 or on the P-gp 28 structures.…”

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Cystic Fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the CFTR chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution EM structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another and both correspond to the inward-facing, NBDs separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel.Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to a NBDs associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data.Moreover, despite different starting points, the final models share many common features.Finally, we propose that the combination of high resolution cryo-EM maps which are currently emerging from multiple labs and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators.

show abstract

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…[13]. In that study, simulations were performed for both the ATP-bound and ATP-unbound (apo) states.…”

Section: Methodsmentioning

confidence: 99%

“…However, in the apo state, the head-to-tail dimer was never formed (see Figure S8 in supporting information of ref. [13]). Here, for each of the two states, the snapshot structures of the two NBD parts were extracted from the MD trajectory data of a corresponding production run at a 50 ps interval taken from ref.…”

Section: Methodsmentioning

confidence: 99%

“…As a result of the NBD dimerization, the CFTR protein is thought to undergo a large structural change from inward-to outward-facing conformations, eventually leading to the opening of the channel. To clarify this mechanism, we recently constructed an atomic model of the inward-facing CFTR in which each ABP is occupied by one ATP molecule and performed MD simulations to explore the structure and dynamics of the inward-facing CFTR in a membrane environment [13]. In the initial structure, the centers of mass (COM) of the two NBDs were separated by approximately 35Å and rapidly approached each other at the start of the MD simulation: within 10 ns, the two NBDs formed a head-to-tail dimer, in which the ATP molecules were sandwiched between the Walker A (WA) and signature (C) motifs.…”

Section: Introductionmentioning

confidence: 99%

“…(B) Time evolution of the inter-motif distances. The atomic coordinates were taken from the MD trajectory data obtained in the previous study [13].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Water-mediated forces between the nucleotide binding domains generate the power stroke in an ABC transporter

Furukawa-Hagiya

Yoshida

Chiba

et al. 2014

Chemical Physics Letters

Self Cite

View full text Add to dashboard Cite

Development of an ATP force field for coarse‐grained simulation of ATPases and its application to the maltose transporter

et al. 2019

Self Cite

View full text Add to dashboard Cite

The biological functions of ATPases, such as myosin, kinesin, and ABC transporter, are due to large conformational motions driven by energy obtained from ATP. Elucidation of the mechanisms underlying these ATP‐driven movements is one of the greatest challenges in computational chemistry. It has been shown that the MARTINI coarse‐grained method is a promising tool for the investigation of large conformational motions in various proteins. However, this method has not yet been applied to ATPases because of the lack of a force field for the ATP molecule. Here, we developed force field parameters for the ATP molecule and conducted simulations using these parameters for the subunits (MalK2) and the full‐length structure (MalFGK2‐E) of a maltose transporter. It was found for both targets that the dimerization of the nucleotide binding domains (NBDs) is induced upon ATP binding. Moreover, for the full‐length transporter, the conformational transition from the pre‐translocation state to the outward‐facing state was observed and was accompanied by an initial transport motion of the substrate. It is expected that coarse‐grained simulations utilizing the parameters for the ATP molecule developed here will serve as a powerful tool for investigating other ATPases as well. © 2019 Wiley Periodicals, Inc.

show abstract

The Power Stroke Driven by ATP Binding in CFTR As Studied by Molecular Dynamics Simulations

Cited by 31 publications

References 91 publications

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Water-mediated forces between the nucleotide binding domains generate the power stroke in an ABC transporter

Development of an ATP force field for coarse‐grained simulation of ATPases and its application to the maltose transporter

Contact Info

Product

Resources

About