Molecular Dynamics Simulations of Acylpeptide Hydrolase Bound to Chlorpyrifosmethyl Oxon and Dichlorvos

Phosphorylation is one of the most frequent post-translational modifications on proteins. It regulates many cellular processes by modulation of phosphorylation on protein structure and dynamics. However, the mechanism of phosphorylation-induced conformational changes of proteins is still poorly understood. Here, we report a computational study of three representative groups of tyrosine in ADP-ribosylhydrolase 1, serine in BTG2, and serine in Sp100C by using six molecular dynamics (MD) simulations and quantum chemical calculations. Added phosphorylation was found to disrupt hydrogen bond (H-bond), and increase new weak interactions (H-bond and hydrophobic interaction) during MD simulations, leading to conformational changes. Quantum chemical calculations further indicate that the phosphorylation on tyrosine, threonine and serine could decrease the optical band gap energy (Egap) energy, which can trigger electronic transitions to form or disrupt interactions easily. Our results provide an atomic and electronic description of how phosphorylation facilitates conformational and dynamic changes in proteins, which may be useful for studying protein function and protein design.

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“…N(omega)-ADP-D-ribosyl)-L-arginine) was downloaded from the Chemspider database and used in Gaussian 09 software at the B3LYP 6–31 G* set. 25 …”

Section: Resultsmentioning

confidence: 99%

“…25–28 Solvation effects were evaluated by single-point calculations on the optimized geometries at the B3LYP 6–31G* level of theory as the geometry optimizations using the conductor-like polarized continuum model (C-PCM). 28 In the calculations, ε = 4 was used for the surrounding solvent.…”

Section: Methodsmentioning

confidence: 99%

Understanding the Phosphorylation Mechanism by Using Quantum Chemical Calculations and Molecular Dynamics Simulations

et al. 2016

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“…In this study, a docking study was conducted to compare the binding mode and energy of trametinib to the ATP pocket and allosteric site of MEK1. As a result, the ligand (trametinib) was docked by AutoDock 4.2 [28,29]. The lowest conformations of MEK1-trametinib complex were selected for further docking analysis ( Figure 1C,D).…”

Section: Binding Mode Of Trametinib To Mek1mentioning

confidence: 99%

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Zhu

Yang

et al. 2020

IJMS

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Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

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“…The electrostatic potential (ESP) on the molecular vdW surface was calculated to investigate and predict intermolecular interactions. The result demonstrated that the strength and orientation of weak interactions, including H bonds and halogen bonds, can be predicted and explained by analyzing the magnitude and positions of the minima and maxima on the surface [ 48 ]. The ESP-mapped vdW surface and the surface extrema of the three ligands are shown in Fig 3A and 3C and 3E ), and the surface areas of the ligands in their different ESP ranges are shown in Fig 3B, 3D and 3F ).…”

Section: Resultsmentioning

confidence: 99%

Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulations

et al. 2018

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Adenosine deaminase (ADA) catalyzes the deamination of adenosine, which is important in purine metabolism. ADA is ubiquitous to almost all human tissues, and ADA abnormalities have been reported in various diseases, including rheumatoid arthritis. ADA can be divided into two conformations based on the inhibitor that it binds to: open and closed forms. Here, we chose three ligands, namely, FR117016 (FR0), FR221647 (FR2) (open form), and HDPR (PRH, closed form), to investigate the inhibition mechanism of ADA and its effect on ADA through molecular dynamics simulations. In open forms, Egap and electrostatic potential (ESP) indicated that electron transfer might occur more easily in FR0 than in FR2. Binding free energy and hydrogen bond occupation revealed that the ADA-FR0 complex had a more stable structure than ADA-FR2. The probability of residues Pro159 to Lys171 of ADA-FR0 and ADA-FR2 to form a helix moderately increased compared with that in nonligated ADA. In comparison with FR0 and FR2 PRH could maintain ADA in a closed form to inhibit the function of ADA. The α7 helix (residues Thr57 to Ala73) of ADA in the closed form was mostly unfastened because of the effect of PRH. The number of H bonds and the relative superiority of the binding free energy indicated that the binding strength of PRH to ADA was significantly lower than that of an open inhibitor, thereby supporting the comparison of the inhibitory activities of the three ligands. Alanine scanning results showed that His17, Gly184, Asp295, and Asp296 exerted the greatest effects on protein energy, suggesting that they played crucial roles in binding to inhibitors. This study served as a theoretical basis for the development of new ADA inhibitors.

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Molecular Dynamics Simulations of Acylpeptide Hydrolase Bound to Chlorpyrifosmethyl Oxon and Dichlorvos

Cited by 22 publications

References 53 publications

Understanding the Phosphorylation Mechanism by Using Quantum Chemical Calculations and Molecular Dynamics Simulations

Understanding the Phosphorylation Mechanism by Using Quantum Chemical Calculations and Molecular Dynamics Simulations

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulations

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