Structural Basis for the Structure–Activity Behaviour of Oxaliplatin and its Enantiomeric Analogues: A Molecular Dynamics Study of Platinum-DNA Intrastrand Crosslink Adducts

2016 ◽  
Vol 69 (4) ◽  
pp. 379 ◽  
Author(s):  
Jing Yang ◽  
Jing Chen ◽  
Zibiao Li
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Conformational Dynamics ◽  
Structural Basis ◽  
Hydrogen Bond Formation ◽  
Damage Recognition ◽  
The Difference ◽  
Highly Correlated ◽  
Dynamics Simulations

The discrimination of Pt-GG adducts by mismatch repair proteins, DNA damage-recognition proteins, and translation DNA polymerases was thought to be vital in determining the toxicity, efficacy, and mutagenicity of platinum anti-tumour drugs. Studies on cis-diammine-Pt-GG (from cisplatin and carboplatin) and trans-R,R-diaminocyclohexane (DACH)-Pt-GG indicated that these proteins recognized the differences in conformation and conformational dynamics of Pt-DNA complexes. However, the structural basis of enantiomeric DACH-Pt-GG forms is unclear. Molecular dynamics simulations results presented here reveal that the conformational dynamics between trans-R,R-DACH-Pt-GG, trans-S,S-DACH-Pt-GG, cis-DACH-Pt-GG and undamaged DNA are distinct and depend on the chirality of DACH though their major conformations are similar. Trans-DACH-Pt was found to be energetically favoured over cis-DACH-Pt to form DNA adducts. Moreover, oxaliplatin and its cis-DACH analogues were found to preferentially form hydrogen bonds on the 3′ side of the Pt-GG adduct, whereas the S,S-DACH-Pt preferred the 5′ side. A three-centre hydrogen bond formed between cis1-DACH-Pt and DNA was observed, and the differences in hydrogen bond formation are highly correlated with differences in DNA conformational dynamics. Based on these results, it is suggested that the different bioactivities of oxaliplatin and its enantiomeric analogues were controlled by the difference in hydrogen bonds formation dynamics between DNA and the Pt moiety. Our molecular dynamics approach was demonstrated to be applicable to the study of stereoisomer conformations of platinum-DNA model, thereby suggesting its potential application as a tool for the study and design of new effective platinum-based drugs.

scholarly journals Car–Parrinello and path integral molecular dynamics study of the intramolecular hydrogen bonds in the crystals of benzoylacetone and dideuterobenzoylacetone

2014 ◽  
Vol 16 (42) ◽  
pp. 23026-23037 ◽  
Author(s):  
Piotr Durlak ◽  
Zdzisław Latajka
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Ab Initio ◽  
Path Integral ◽  
Molecular Crystal ◽  
Short Hydrogen Bond ◽  
Deuterated Analogue ◽  
Dynamics Simulations ◽  
Intramolecular Hydrogen

The dynamics of the intramolecular short hydrogen bond in the molecular crystal of benzoylacetone and its deuterated analogue are investigated using ab initio molecular dynamics simulations.

Molecular dynamics simulations of N-methylacetamide (NMA) in water by the ABEEM/MM model

2009 ◽  
Vol 87 (12) ◽  
pp. 1738-1746 ◽  
Author(s):  
Ping Qian ◽  
Li-Nan Lu ◽  
Zhong-Zhi Yang
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Potential Model ◽  
Lone Pair ◽  
Static Properties ◽  
Range Interaction ◽  
Hydrogen Bond Interaction ◽  
Lone Pair Electron ◽  
Dynamics Simulations

The N-methylacetamide (NMA) is a very interesting kind of compound and often serves as a model of the peptide bond. The interaction between NMA and water provides a convenient prototype for the solvation of peptides in aqueous solutions. We have carried out molecular dynamics (MD) simulations of a NMA molecule in water under 1 atm and 298 K. The simulations make use of the newly developed NMA–water fluctuating charge ABEEM/MM potential model ( Yang, Z. Z.; Qian, P. J. Chem. Phys. 2006, 125, 064311 ), which is based on the combination of the atom-bond electronegativity equalization method (ABEEM) and molecular mechanics (MM). This model has been successfully applied to NMA–water gas clusters, NMA(H2O)n (n = 1–6), and accurately reproduced many static properties. For the NMA–water ABEEM/MM potential model, two characters must be emphasized in the simulations. Firstly, the model allows the charges in system to fluctuate, responding to the ambient environment. Secondly, for two major types of intermolecular hydrogen bonds, which are the hydrogen bond forming between the lone-pair electron on amide oxygen and the water hydrogen, and the one forming between the lone-pair electron on water oxygen and the amide hydrogen, we take special treatments in describing the electrostatic interaction by the use of the parameters klpO=,H and klpO–,HN–, respectively, which explicitly describe the short-range interaction of hydrogen bonds in the hydrogen bond interaction region. All sorts of properties have been studied in detail, such as, radial distribution function, energy distribution, ABEEM charge distribution and dipole moment, and so on. These simulation results show that the ABEEM/MM-based NMA–water potential model appears to be robust, giving the solution properties in excellent agreement with other dynamics simulations on similar systems.

scholarly journals Molecular Dynamics Simulation of VEGFR2 with Sorafenib and Other Urea-Substituted Aryloxy Compounds

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Fancui Meng
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Dynamics Simulation ◽  
Hydrogen Bonds ◽  
Md Simulation ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Dynamics Simulations ◽  
Simulation Time ◽  
Dynamics Method

The binding mode of sorafenib with VEGFR2 was studied using molecular docking and molecular dynamics method. The docking results show that sorafenib forms hydrogen bonds with Asp1046, Cys919, and Glu885 of VEGFR2 receptor. Molecular dynamics simulation suggests that the hydrogen bond involving Asp1046 is the most stable one, and it is almost preserved during all the MD simulation time. The hydrogen bond formed with Cys919 occurs frequently after 6 ns, while the bifurcated hydrogen bonds involving Glu885 occurs occasionally. Meantime, molecular dynamics simulations of VEGFR2 with 11 other urea-substituted aryloxy compounds have also been performed, and the results indicate that a potent VEGFR2 inhibitor should have lower interaction energy with VEGFR2 and create at least 2 hydrogen bonds with VEGFR2.

scholarly journals Molecular Dynamics Simulations of Heterogeneous Hydrogen Bond Environment in Hydrophobic Deep Eutectic Solvents

2021 ◽  
Author(s):  
Usman Abbas ◽  
Manh Tien Nguyen ◽  
Qi Qiao ◽  
Jian Shi ◽  
Qing Shao
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Molecular Dynamics Simulations ◽  
High Performance ◽  
Deep Eutectic Solvents ◽  
Decanoic Acid ◽  
Hydrogen Bond Strength ◽  
Multiple Hydrogen Bond ◽  
Dynamics Simulations

Hydrophobic deep eutectic solvents (DESs) have emerged as excellent extractants. Their performance depends on the heterogeneous hydrogen bond environment formed by multiple hydrogen bond donors and acceptors. An understanding of this heterogeneous hydrogen bond environment can be used to develop principles for designing high-performance DESs for extraction and other separation applications. We investigate the structure and dynamics of hydrogen bonds in eight hydrophobic DESs formed by decanoic acid, menthol, thymol, and Lidocaine using molecular dynamics simulations. The results show the diversity of hydrogen bonds in the eight DESs and their impact on diffusivity and molecular association. Each DES possesses four-six types of hydrogen bonds and one or two of them overwhelm the others in quantity and lifetime. The dominating hydrogen bonds determine whether the DESs are governed by intra- or inter-component associations. The component diffusivity presents an inverse relationship with the hydrogen bond strength.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
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>

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

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
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.

WHICH IS THE PROTON-SHUTTLE IN ISOXANTHOPTERIN DEAMINASE? QM/MM MD UNDERSTANDING

2013 ◽  
Vol 12 (08) ◽  
pp. 1341002 ◽  
Author(s):  
XIN ZHANG ◽  
MING LEI
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Proton Transfer ◽  
Glutamic Acid ◽  
Active Site ◽  
Nucleophilic Attack ◽  
Zinc Ions ◽  
Initial Model ◽  
Dynamics Simulations

The deamination process of isoxanthopterin catalyzed by isoxanthopterin deaminase was determined using the combined QM(PM3)/MM molecular dynamics simulations. In this paper, the updated PM3 parameters were employed for zinc ions and the initial model was built up based on the crystal structure. Proton transfer and following steps have been investigated in two paths: Asp336 and His285 serve as the proton shuttle, respectively. Our simulations showed that His285 is more effective than Aap336 in proton transfer for deamination of isoxanthopterin. As hydrogen bonds between the substrate and surrounding residues play a key role in nucleophilic attack, we suggested mutating Thr195 to glutamic acid, which could enhance the hydrogen bonds and help isoxanthopterin get close to the active site. The simulations which change the substrate to pterin 6-carboxylate also performed for comparison. Our results provide reference for understanding of the mechanism of deaminase and for enhancing the deamination rate of isoxanthopterin deaminase.

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