MD investigation on the binding of microphthalmia-associated transcription factor with DNA

Wang, Xiangfeng; Sun, Jian; Tian, Jiakun; Tian, Zhen-Wei; Zhang, Jilong; Jia, Ran

doi:10.1016/j.jscs.2022.101420

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…To get insight into the interactions between the ligand and the enzyme, binding free energy of two complex systems was calculated by the MM-PB/SA method in Amber16, and the contribution of entropy was also considered [42,43]. An amount of 5000 frames is uniformly selected from the last 100 ns trajectory of equilibrium for calculation, and the results are listed in Table 4.…”

Section: Binding Free Energy Analysismentioning

confidence: 99%

Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5

Liu,

Zheng,

Bai

2023

Molecules

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CYP 3A4 and CYP 3A5 are two important members of the human cytochrome P450 family. Although their overall structures are similar, the local structures of the active site are different, which directly leads to obvious individual differences in drug metabolic efficacy and toxicity. In this work, midazolam (MDZ) was selected as the probe substrate, and its interaction with two proteins, CYP 3A4 and CYP 3A5, was studied by molecular dynamics simulation (MD) along with the calculation of the binding free energy. The results show that two protein–substrate complexes have some similarities in enzyme–substrate binding; that is, in both complexes, Ser119 forms a high occupancy hydrogen bond with MDZ, which plays a key role in the stability of the interaction between MDZ and the enzymes. However, the complex formed by CYP 3A4 and MDZ is more stable, which may be attributed to the sandwich structure formed by the fluorophenyl group of the substrate with Leu216 and Leu482. Our study interprets the binding differences between two isoform–substrate complexes and reveals a structure–function relationship from the atomic perspective, which is expected to provide a theoretical basis for accurately measuring the effectiveness and toxicity of drugs for individuals in the era of precision medicine.

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Section: Binding Free Energy Analysismentioning

confidence: 99%

Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5

Liu,

Zheng,

Bai

2023

Molecules

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“…Among the current tools for probing the conformational dynamics of targets, conventional molecular dynamics (cMD) [42][43][44][45][46][47][48], Gaussian accelerated molecular dynamics (GaMD) simulations [49][50][51], and analysis of binding free energy [52][53][54][55][56][57] have been extensively used to reveal the molecular mechanisms and free energy profiles underlying conformational changes. Compared to cMD simulations, GaMD simulations more easily overcome energy barriers in protein systems.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning

Chen,

Wang,

Yang

et al. 2024

Molecules

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The phosphorylation of different sites produces a significant effect on the conformational dynamics of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations were combined with deep learning (DL) to explore the molecular mechanism of the phosphorylation-mediated effect on conformational dynamics of the GTP-bound KRAS. The DL finds that the switch domains are involved in obvious differences in conformation contacts and suggests that the switch domains play a key role in the function of KRAS. The analyses of free energy landscapes (FELs) reveal that the phosphorylation of pY32, pY64, and pY137 leads to more disordered states of the switch domains than the wild-type (WT) KRAS and induces conformational transformations between the closed and open states. The results from principal component analysis (PCA) indicate that principal motions PC1 and PC2 are responsible for the closed and open states of the phosphorylated KRAS. Interaction networks were analyzed and the results verify that the phosphorylation alters interactions of GTP and magnesium ion Mg2+ with the switch domains. It is concluded that the phosphorylation pY32, pY64, and pY137 tune the activity of KRAS through changing conformational dynamics and interactions of the switch domains. We anticipated that this work could provide theoretical aids for deeply understanding the function of KRAS.

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“…However, so far, there is no relevant report on the details of the EphA6–Odin protein complex formation process. Therefore, in this study, we investigated the detailed binding process of EphA6 and its ligand protein Odin, as well as the dynamics and energetics behind their interaction, by several simulation techniques such as conventional molecular dynamics simulation and umbrella sampling simulation, which have been proven to be powerful in solving similar protein–ligand-binding or unbinding issues. − Based on steered molecular dynamics (SMD), the potential of mean force (PMF) of the protein-binding process was obtained by the umbrella sampling simulation, and the conformation changes of the receptor and ligand protein during the binding process were revealed. The MD results present a dynamic binding view of EphA6 and Odin and provide important insights into the interaction of such protein macromolecules.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulation Investigation of the Binding and Interaction of the EphA6–Odin Protein Complex

Zhou

Zhang

et al. 2022

J. Phys. Chem. B

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Protein–protein interaction plays an important role in the development of almost all cells. Elucidating the dynamic binding and affinity of a protein–protein complex is essential for understanding the biological functions of proteins. EphA6 and Odin proteins are members of the Eph (erythropoietin-producing hepatocyte) receptor family and the Anks (ankyrin repeat and sterile α motif domain-containing) family, respectively. Odin significantly functions in regulating endocytosis, degradation, and stability of EphA receptors. In this work, the key residues of the interaction interface were determined through a hydrogen bond, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and dynamic correlation analysis of the conventional molecular dynamics (MD) simulations. The calculated standard binding free energy, −7.92 kcal/mol, between EphA6 and Odin is quite consistent with the experimental measurement value, −8.73 kcal/mol. By the combination of several MD simulation techniques, our investigation of the binding process reveals the detailed representative characteristics of the entire binding pathway at the molecular level. Based on the obtained potential of the mean force (PMF) curve, the analysis of the simulation trajectories shows that the residue Arg1013 in the receptor EphA6 is responsible for capturing Asp739 and Asp740 in the ligand Odin during the initial stage of binding. In the later stage of binding, the hydrogen bonds and salt bridges between a series of residues Lys973, Leu1007, Gly1009, His1010, and Arg1012 in the receptor and residues Leu735, Asn736, Asp739, Asp740, and Asp753 in the ligand mainly contribute to the stability of the protein complex. In addition, the specific change process of the receptor–ligand-binding mode is also clarified during the binding process. Our present simulation will promote a deep understanding of the protein–protein interaction, and the identified key interresidue interaction will be theoretical guidance for the design of protein drugs.

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MD investigation on the binding of microphthalmia-associated transcription factor with DNA

Cited by 3 publications

References 51 publications

Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5

Differences of Atomic-Level Interactions between Midazolam and Two CYP Isoforms 3A4 and 3A5

Molecular Mechanism of Phosphorylation-Mediated Impacts on the Conformation Dynamics of GTP-Bound KRAS Probed by GaMD Trajectory-Based Deep Learning

Molecular Dynamics Simulation Investigation of the Binding and Interaction of the EphA6–Odin Protein Complex

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