Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

Chen, Jianzhong; Zhang, Dinglin; Zhang, Yuxin; Li, Guohui

doi:10.3390/ijms13022176

Cited by 22 publications

(17 citation statements)

References 64 publications

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“…The decomposition approach is extremely useful to locate the residues, which contribute to the protein-protein and protein-ligand interactions [29–31]. The residues with the absolute free energies contribution larger than 1 kcal/mol for the protein-residue are labeled (Figure 4b,c).…”

Section: Resultsmentioning

confidence: 99%

Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation

Liu

et al. 2014

IJMS

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14-3-3σ is a member of a highly conserved family of 14-3-3 proteins that has a double-edged sword role in human cancers. Former reports have indicated that the 14-3-3 protein may be in an open or closed state. In this work, we found that the apo-14-3-3σ is in an open state compared with the phosphopeptide bound 14-3-3σ complex which is in a more closed state based on our 80 ns molecular dynamics (MD) simulations. The interaction between the two monomers of 14-3-3σ in the open state is the same as that in the closed state. In both open and closed states, helices A to D, which are involved in dimerization, are stable. However, large differences are found in helices E and F. The hydrophobic contacts and hydrogen bonds between helices E and G in apo-14-3-3σ are different from those in the bound 14-3-3σ complex. The restrained and the mutated (Arg56 or Arg129 to alanine) MD simulations indicate that the conformation of four residues (Lys49, Arg56, Arg129 and Tyr130) may play an important role to keep the 14-3-3σ protein in an open or closed state. These results would be useful to evaluate the 14-3-3σ protein structure-function relationship.

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Section: Resultsmentioning

confidence: 99%

Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation

Liu

et al. 2014

IJMS

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“…An appropriate number of chloride counter ions were placed around four TPH1–inhibitor complexes to neutralize the charges of the systems. Finally, the whole system was solvated in a cubic periodic box of TIP3P water molecules, and the distance between the edges of the water box and the closest atom of the solutes was at least 10 Å [26–28]. To avoid edge effects, periodic boundary conditions were applied during the whole molecular dynamics (MD) simulation.…”

Section: Methodsmentioning

confidence: 99%

Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors

Huang

Peng

et al. 2013

IJMS

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Serotonin is a neurotransmitter that modulates many central and peripheral functions. Tryptophan hydroxylase-1 (TPH1) is a key enzyme of serotonin synthesis. In the current study, the interaction mechanism of phenylalanine derivative TPH1 inhibitors was investigated using molecular dynamics (MD) simulations, free energy calculations, free energy decomposition analysis and computational alanine scanning. The predicted binding free energies of these complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals and electrostatics interaction contributions are important in distinguishing the binding affinities of these inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the naphthalene substituent could form different binding patterns with protein, yet lead to similar inhibitory potency. The combination of different molecular modeling techniques is an efficient way to interpret the interaction mechanism of inhibitors and our work could provide valuable information for the TPH1 inhibitor design in the future.

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“…Computational investigations of protein conformational changes and ligand binding events have become indispensable tools to provide the atomic description of protein functions for the experimental observations 44 45 46 47 . However, sampling large-scale conformational space of the protein dynamic and acquiring the energetic profile of a ligand binding process in standard molecular dynamic (MD) simulations are still challenging tasks.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insight into the functional transition of the enzyme guanylate kinase induced by a single mutation

Zhang

Huang

Yan

et al. 2015

Sci Rep

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Dramatic functional changes of enzyme usually require scores of alterations in amino acid sequence. However, in the case of guanylate kinase (GK), the functional novelty is induced by a single (S→P) mutation, leading to the functional transition of the enzyme from a phosphoryl transfer kinase into a phosphorprotein interaction domain. Here, by using molecular dynamic (MD) and metadynamics simulations, we provide a comprehensive description of the conformational transitions of the enzyme after mutating serine to proline. Our results suggest that the serine plays a crucial role in maintaining the closed conformation of wild-type GK and the GMP recognition. On the contrary, the S→P mutant exhibits a stable open conformation and loses the ability of ligand binding, which explains its functional transition from the GK enzyme to the GK domain. Furthermore, the free energy profiles (FEPs) obtained by metadymanics clearly demonstrate that the open-closed conformational transition in WT GK is positive correlated with the process of GMP binding, indicating the GMP-induced closing motion of GK enzyme, which is not observed in the mutant. In addition, the FEPs show that the S→P mutation can also leads to the mis-recognition of GMP, explaining the vanishing of catalytic activity of the mutant.

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Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

Cited by 22 publications

References 64 publications

Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation

Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation

Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors

Mechanistic insight into the functional transition of the enzyme guanylate kinase induced by a single mutation

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