Molecular dynamics simulations of the conformational changes of the glutamate receptor ligand-binding core in the presence of glutamate and kainate

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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Molecular mechanism concerning conformational changes of CDK2 mediated by binding of inhibitors using molecular dynamics simulations and principal component analysis

SAR and QSAR in Environmental Research ◽

10.1080/1062936x.2021.1934896 ◽

2021 ◽

pp. 1-22

Author(s):

S.S. Liang ◽

X.G. Liu ◽

Y.X. Cui ◽

S.L. Zhang ◽

Q.G. Zhang ◽

...

Keyword(s):

Molecular Dynamics ◽

Principal Component Analysis ◽

Molecular Dynamics Simulations ◽

Molecular Mechanism ◽

Conformational Changes ◽

Principal Component ◽

Component Analysis ◽

Dynamics Simulations

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Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

International Journal of Molecular Sciences ◽

10.3390/ijms22136709 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6709

Author(s):

Xiao-Xuan Shi ◽

Peng-Ye Wang ◽

Hong Chen ◽

Ping Xie

Keyword(s):

Molecular Dynamics ◽

High Resolution ◽

Binding Energy ◽

Molecular Dynamics Simulations ◽

Conformational Changes ◽

Weak Interactions ◽

Molecular Motor ◽

Structural Data ◽

Calculated Binding Energy ◽

Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

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High Level Production, Characterization and Construct Optimization of the Ionotropic Glutamate Receptor Ligand Binding Core

Tetrahedron ◽

10.1016/s0040-4020(00)00825-5 ◽

2000 ◽

Vol 56 (48) ◽

pp. 9409-9419 ◽

Cited By ~ 2

Author(s):

Guo Qiang Chen ◽

Eric Gouaux

Keyword(s):

Ligand Binding ◽

Glutamate Receptor ◽

Ionotropic Glutamate Receptor ◽

Receptor Ligand ◽

Construct Optimization ◽

Binding Core ◽

High Level ◽

Level Production

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The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽

10.3390/molecules26051250 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1250

Author(s):

Hien T. T. Lai ◽

Alejandro Giorgetti ◽

Giulia Rossetti ◽

Toan T. Nguyen ◽

Paolo Carloni ◽

...

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Molecular Dynamics Simulations ◽

Binding Site ◽

Transmembrane Protein ◽

Free Form ◽

Experimental Investigations ◽

Terminal Part ◽

Dynamics Simulations ◽

Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

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