Molecular dynamics simulations on apo ADP/ATP carrier shed new lights on the featured motif of the mitochondrial carriers

Yi, Qiuzi; Li, Qiang; Yao, Shihao; Chen, Ye; Guan, Min‐Xin; Cang, Xiaohui

doi:10.1016/j.mito.2019.05.006

Cited by 15 publications

(51 citation statements)

References 53 publications

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“…Three 3-μs trajectories of apo-AAC were taken from our previous work [7]. Snapshots were taken from 2 μs till the end of the simulation with an interval of 100 ns.…”

Section: Large Scale Short MD Simulations On Adp Bindingmentioning

confidence: 99%

“…For comparison purpose, five simulations were also carried out on ATP binding. The ten simulations started from the same conformation of the carrier taken from the last snapshot of one trajectory in our previous work [7], but with different orientations in ADP or ATP. Other simulations protocols are the same as the short ones as described above.…”

Section: Microsecond-timescale Simulations On Adp Binding and Atp Bindingmentioning

confidence: 99%

“…We first carried out large-scale short MD simulations (S1~S33, each 10 ns long) to investigate initial ADP binding steps to the ground c-state AAC. To reduce bias, initial conformations of the carrier were picked evenly from the last 1 μs trajectories in our previous three 3-μs simulations on apo-AAC [7], and ADP was placed in a random orientation above the pocket entrance. The results show that in 30 out of 33 simulations, ADP was quickly (within 1 ns on average) attracted to the positive residues in the upper region of the cavity, with the highest first-contact frequencies observed on residues K205, K198, K95 and K91.…”

Section: Large-scale Short MD Simulations Reveal Initial Adp Binding Steps To C-state Aacmentioning

confidence: 99%

“…It's especially powerful in elucidating structure-function relationship for those functionally important model molecules like AAC, for which a huge body of previous experimental results can serve as validations and provide guidance to better interpret the simulation results. Previously we used this technique to improve our understandings on the conserved MCF motif and cardiolipin binding sites of AAC [7,24]. In the current work, spontaneous ADP binding process to c-state bovine AAC1 was investigated through rigorous MD simulations of up to 22 μs in total.…”

Section: Introductionmentioning

confidence: 99%

“…MCF transporters are special for their small size and for having three homologous domains instead of two. Each domain is about 100 aa long and contains highly conserved MCF motif: Pxx[D/E]xx[K/R]xR-(20-30 residues)- [6,7], and these motif residues determine the common structural scaffold of this family. Despite similar structures of these transporters, their substrates are extremely diverse, ranging from very small proton to very large Coenzyme A (CoA) and NAD + .…”

Section: Introductionmentioning

confidence: 99%

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Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter

Yao

et al. 2021

Preprint

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Specific import of ADP and export of ATP by ADP/ATP carrier (AAC) across the inner mitochondrial membrane are crucial for sustainable energy supply in all eukaryotes. However, mechanism for highly specific substrate recognition in the dynamic transport process remains largely elusive. Here, unguided MD simulations of 22 microseconds in total reveal that AAC in ground c-state uses the second basic patch (K91K95R187), tyrosine ladder (Y186Y190Y194), F191 and N115 in the upper region of the cavity to specifically recognize ADP and confer selectivity for ADP over ATP. Mutations of these residues in yeast AAC2 reduce ADP transport across the L. lactis membrane and induce defects in OXPHOS and ATP production in yeast. Sequence analyses also suggest that AAC and other adenine nucleotide transporters use the upper region of the cavity, rather than the central binding site to discriminate their substrates. Identification of the new site unveils the unusually high substrate specificity of AAC, and together with central binding site support early biochemical findings about existence of two substrate binding sites. Our results imply that using different sites for substrate recognition and conformational transition could be a smart strategy for transporters to cope with substrate recognition problem in the highly dynamic transport process.

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“…Three 3-μs trajectories of apo-AAC were taken from our previous work [7]. Snapshots were taken from 2 μs till the end of the simulation with an interval of 100 ns.…”

Section: Large Scale Short MD Simulations On Adp Bindingmentioning

confidence: 99%

Section: Microsecond-timescale Simulations On Adp Binding and Atp Bindingmentioning

confidence: 99%

Section: Large-scale Short MD Simulations Reveal Initial Adp Binding Steps To C-state Aacmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter

Yao

et al. 2021

Preprint

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Molecular Dynamics Simulations of the Elusive Matrix‐Open State of Mitochondrial ADP/ATP Carrier

Škulj

Brkljača

Vazdar

2020

Israel Journal of Chemistry

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We studied and compared in detail an elusive matrix open (m‐state) and cytoplasmic open (c‐state) state of ADP/ATP carrier (AAC) protein embedded in the DOPC bilayer by microsecond molecular dynamics (MD) simulations. We analyzed both states with and without cardiolipin (CDL) molecules, with a special emphasis on the recently obtained crystallographic structure of the AAC m‐state. The obtained results show that both states of the protein are stable in the DOPC bilayer and impermeable to water. In comparison with the c‐state of AAC, the m‐state is more dynamic, but at the same time possesses a larger occluded area in the protein cavity. Both states of the protein are less flexible in simulations when CDL molecules are present, which is especially visible for the m‐state. Finally, the analysis of the protein conformational changes during MD simulations shows that protein parts at the protein/lipid boundaries are prone to larger conformational changes in contrast to central region of the protein embedded in the bilayer core, thus further supporting the cycling mechanism suggested for ADP/ATP exchange by AAC.

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Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier

Mao

Yao

et al. 2021

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Molecular dynamics simulations on apo ADP/ATP carrier shed new lights on the featured motif of the mitochondrial carriers

Cited by 15 publications

References 53 publications

Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter

Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter

Molecular Dynamics Simulations of the Elusive Matrix‐Open State of Mitochondrial ADP/ATP Carrier

Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier

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