Substrate recognition and transport behavior analyses of amino acid antiporter with coarse-grained models

Chang, Shan; Hu, Jianping; Lin, Piyuan; Jiao, Xiong; Tian, Xin

doi:10.1039/c005266c

Cited by 32 publications

(26 citation statements)

References 43 publications

(57 reference statements)

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“…Another effect of Glu208 − is that it diminishes the persistence of the cation-π interaction between the Gdm + group of the divalent ligands and the middle gate residue Trp293 whereas it increases this interaction persistence for monovalent Arg + (Table 1 ). This gating residue is known to be crucial for AdiC activity 19 , 20 , 34 (Table 1 ). The decreased persistence of this interaction in the case of Arg 2+ and Agm 2+ correlates with their shorter residence time.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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“…As regards the AR antiporters, the AdiC structures trapped in the arginine-free or arginine-bound OF open conformations and those trapped in the occluded arginine-bound conformation [ 14 , 15 , 25 , 26 ], along with the structure of GadC determined in an IF open substrate-free conformation [ 27 ], open the way to using MD to study the mechanism of substrate transport in AR systems at the atomic level. To the best of our knowledge, so far only a few MD and modeling studies have been performed on AdiC [ 15 , 50 , 51 ]. Notably, an MD study exploiting crystallographic and docking data has pointed to the involvement of several residues in proper coordination of the ligand and in occlusion of the binding site to the OF open state [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Mechanism of Arginine Transport through AdiC with Molecular Dynamics Simulations: The Guiding Role of Aromatic Residues

et al. 2016

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Commensal and pathogenic enteric bacteria have developed several systems to adapt to proton leakage into the cytoplasm resulting from extreme acidic conditions. One such system involves arginine uptake followed by export of the decarboxylated product agmatine, carried out by the arginine/agmatine antiporter (AdiC), which thus works as a virtual proton pump. Here, using classical and targeted molecular dynamics, we investigated at the atomic level the mechanism of arginine transport through AdiC of E. coli. Overall, our MD simulation data clearly demonstrate that global rearrangements of several transmembrane segments are necessary but not sufficient for achieving transitions between structural states along the arginine translocation pathway. In particular, local structural changes, namely rotameric conversions of two aromatic residues, are needed to regulate access to both the outward- and inward-facing states. Our simulations have also enabled identification of a few residues, overwhelmingly aromatic, which are essential to guiding arginine in the course of its translocation. Most of them belong to gating elements whose coordinated motions contribute to the alternating access mechanism. Their conservation in all known E. coli acid resistance antiporters suggests that the transport mechanisms of these systems share common features. Last but not least, knowledge of the functional properties of AdiC can advance our understanding of the members of the amino acid-carbocation-polyamine superfamily, notably in eukaryotic cells.

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“…36,37 On the basis of the above dynamical cross-correlated analysis, the covariance matrix C is diagonalized to obtain the orthogonal eigenvectors and the corresponding eigenvalues. The eigenvectors are also called the principal components (PCs), which indicate the directions of the concerted mot ions.…”

Section: Principal Component Analysismentioning

confidence: 99%

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

Chang

Zhang

et al. 2016

RNA Biology

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RNA-binding protein with multiple splicing (RBPMS) is critical for axon guidance, smooth muscle plasticity, and regulation of cancer cell proliferation and migration. Recently, different states of the RNA-recognition motif (RRM) of RBPMS, one in its free form and another in complex with CAC-containing RNA, were determined by Xray crystallography. In this article, the free RRM domain, its wild type complex and 2 mutant complex systems are studied by molecular dynamics (MD) simulations. Through comparison of free RRM domain and complex systems, it's found that the RNA binding facilitates stabilizing the RNA-binding interface of RRM domain, especially the C-terminal loop. Although both R38Q and T103A/K104A mutations reduce the binding affinity of RRM domain and RNA, the underlining mechanisms are different. Principal component analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) methods were used to explore the dynamical and recognition mechanisms of RRM domain and RNA. R38Q mutation is positioned on the homodimerization interface and mainly induces the large fluctuations of RRM domains. This mutation does not directly act on the RNA-binding interface, but some interfacial hydrogen bonds are weakened. In contrast, T103A/K104A mutations are located on the RNA-binding interface of RRM domain. These mutations obviously break most of high occupancy hydrogen bonds in the RNA-binding interface. Meanwhile, the key interfacial residues lose their favorable energy contributions upon RNA binding. The ranking of calculated binding energies in 3 complex systems is well consistent with that of experimental binding affinities. These results will be helpful in understanding the RNA recognition mechanisms of RRM domain.

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Substrate recognition and transport behavior analyses of amino acid antiporter with coarse-grained models

Cited by 32 publications

References 43 publications

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Unveiling the Mechanism of Arginine Transport through AdiC with Molecular Dynamics Simulations: The Guiding Role of Aromatic Residues

Exploring the molecular basis of RNA recognition by the dimeric RNA-binding protein via molecular simulation methods

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