MOLECULAR SIMULATIONS OF NEOCARZINOSTATIN CHROMOPHORE RELEASE MECHANISM

Neocarzinostatin (NCS) is an antitumor chromophore carrier protein with many applications in clinical use such as drug delivery system; however, so far its chromophore-releasing mechanism remains unclear. In this contribution the process and pathway of the chromophore releasing from holoprotein are revealed by conventional molecular dynamics simulations and essential dynamics (ED) sampling method. The results are consistent with the model for ligand release proposed in [D. H. Chin et al., J Biol Chem281:16025, 2006]. The further analysis suggests that the conformational changes of loop 99–104 and motions of side-chain of residue Phe78 are important factors for chromophore release; the opening state of loop 99–104 is a precondition for the release of ligand.

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How low-resolution structural data predict the conformational changes of a protein: a study on data-driven molecular dynamics simulations

Physical Chemistry Chemical Physics ◽

10.1039/c8cp02246a ◽

2018 ◽

Vol 20 (26) ◽

pp. 17790-17798 ◽

Cited By ~ 2

Author(s):

Ryuhei Harada ◽

Yasuteru Shigeta

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Conformational Changes ◽

Sampling Method ◽

Protein A ◽

Structural Data ◽

Data Driven ◽

Conformational Sampling ◽

Transition Pathways ◽

Dynamics Simulations

Parallel cascade selection molecular dynamics (PaCS-MD) is a conformational sampling method for generating transition pathways between a given reactant and a product.

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Molecular Basis of Glucose Transport Mechanism in Plants

10.26434/chemrxiv.8049848.v1 ◽

2019 ◽

Cited By ~ 2

Author(s):

Balaji Selvam ◽

Ya-Chi Yu ◽

Liqing Chen ◽

Diwakar Shukla

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Dynamics Simulations ◽

Conformational Changes ◽

Transport Mechanism ◽

Conformational Dynamics ◽

Site Directed Mutagenesis ◽

Free Energy Barrier ◽

Transport Cycle ◽

Dynamics Simulations

<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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Faculty Opinions recommendation of Coupling between side chain interactions and binding pocket flexibility in HLA-B*44:02 molecules investigated by molecular dynamics simulations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718542946.793528448 ◽

2017 ◽

Author(s):

Tim Elliott ◽

Andy van Hateren

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Binding Pocket ◽

Side Chain ◽

Dynamics Simulations

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Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

Current Computer - Aided Drug Design ◽

10.2174/1573409915666190708103132 ◽

2020 ◽

Vol 16 (4) ◽

pp. 451-459 ◽

Cited By ~ 1

Author(s):

Fortunatus C. Ezebuo ◽

Ikemefuna C. Uzochukwu

Keyword(s):

Molecular Dynamics ◽

Amino Acid ◽

Binding Energy ◽

Binding Site ◽

Conformational Dynamics ◽

Side Chain ◽

Amino Acid Residues ◽

Conformational Selection ◽

Hybrid Mechanism ◽

Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

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

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.1111 ◽

2001 ◽

Vol 44 (4) ◽

pp. 460-469 ◽

Cited By ~ 28

Author(s):

Jesús Mendieta ◽

Galo Ramírez ◽

Federico Gago

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Molecular Dynamics Simulations ◽

Glutamate Receptor ◽

Conformational Changes ◽

Receptor Ligand ◽

Binding Core ◽

Dynamics Simulations

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On the dynamics of some small structural motifs in rRNA upon ligand binding

Journal of the Serbian Chemical Society ◽

10.2298/jsc0801041r ◽

2008 ◽

Vol 73 (1) ◽

pp. 41-53

Author(s):

Aleksandra Rakic ◽

Petar Mitrasinovic

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Binding Sites ◽

De Novo ◽

Reference Structure ◽

Base Pairs ◽

Rna Sequences ◽

Conformational Model ◽

Thermodynamic Variables ◽

Dynamics Simulations

The present study characterizes using molecular dynamics simulations the behavior of the GAA (1186-1188) hairpin triloops with their closing c-g base pairs in large ribonucleoligand complexes (PDB IDs: 1njn, 1nwy, 1jzx). The relative energies of the motifs in the complexes with respect to that in the reference structure (unbound form of rRNA; PDB ID: 1njp) display the trends that agree with those of the conformational parameters reported in a previous study1 utilizing the de novo pseudotorsional (?,?) approach. The RNA regions around the actual RNA-ligand contacts, which experience the most substantial conformational changes upon formation of the complexes were identified. The thermodynamic parameters, based on a two-state conformational model of RNA sequences containing 15, 21 and 27 nucleotides in the immediate vicinity of the particular binding sites, were evaluated. From a more structural standpoint, the strain of a triloop, being far from the specific contacts and interacting primarily with other parts of the ribosome, was established as a structural feature which conforms to the trend of the average values of the thermodynamic variables corresponding to the three motifs defined by the 15-, 21- and 27-nucleotide sequences. From a more functional standpoint, RNA-ligand recognition is suggested to be presumably dictated by the types of ligands in the complexes.

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