Parallel Cascade Selection Molecular Dynamics Simulations for Transition Pathway Sampling of Biomolecules

Harada, Ryuhei; Shigeta, Yasuteru

doi:10.1016/bs.aiq.2018.05.002

Cited by 2 publications

(2 citation statements)

References 45 publications

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“…Here, we used the inter-center of mass distance (inter-COM distance, d ) between p53-DBD and DNA as a quantity for ranking the snapshots generated in each cycle. By repeating a series of cycles for the selected top-ranked snapshots, dissociation PaCS-MD (dPaCS-MD) generates structures with larger inter-COM distances than those found in the previous cycle, which significantly enhances the probability of transitions from the bound to unbound states. ,, Short MD trajectories, a series of molecular configurations, connect the initial bound and final unbound states along the dissociation pathways, and the MD trajectories from many trials of dPaCS-MD can be combined to generate different dissociation pathways, which mutually overlap in conformational space. Using these trajectories, we can construct an MSM which describes the dynamics of a biochemical process as a sequence of transitions between metastable conformational states (microstates). − Our group recently established the dPaCS-MD/MSM combination to simulate protein–ligand and protein–protein fragment , dissociation and to accurately calculate ΔG° in good agreement with experimental values.…”

Section: Introductionmentioning

confidence: 99%

Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM

Sobeh

Kitao

2022

J. Chem. Inf. Model.

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p53 is a transcriptional factor that regulates cell response to a variety of stresses. About a half of all human tumors contain p53 mutations, and the accumulation of mutations in the DNA binding domain of p53 (p53-DBD) can cause destabilization of p53 and its complex with DNA. To identify the key residues of the p53-DBD/DNA binding and to understand the dissociation mechanisms of the p53-DBD/DNA complex, the dissociation process of p53-DBD from a DNA duplex that contains the consensus sequence (the specific target of p53-DBD) was investigated by a combination of dissociation parallel cascade selection molecular dynamics (dPaCS-MD) and the Markov state model (MSM). This combination (dPaCS-MD/MSM) enabled us to simulate dissociation of the two large molecules based on an all-atom model with a short simulation time (11.2 ± 2.2 ns per trial) and to analyze dissociation pathways, free energy landscape (FEL), and binding free energy. Among 75 trials of dPaCS-MD, p53-DBD dissociated first from the major groove and then detached from the minor groove in 93% of the cases, while 7% of the cases unbinding from the minor groove occurred first. Minor groove binding is mainly stabilized by R248, identified as the most important residue that tightly binds deep inside the minor groove. The standard binding free energy calculated from the FEL was −10.9 ± 0.4 kcal/mol, which agrees with an experimental value of −11.1 kcal/mol. These results indicate that the dPaCS-MD/MSM combination can be a powerful tool to investigate dissociation mechanisms of two large molecules. Analysis of the p53 key residues for DNA binding indicates high correlations with cancer-related mutations, confirming that impairment of the interactions between p53-DBD and DNA can be frequently related to cancer.

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Section: Introductionmentioning

confidence: 99%

Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM

Sobeh

Kitao

2022

J. Chem. Inf. Model.

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“…Here, we used the inter-center of mass distance between p53-DBD and DNA (Inter-COM distance, d) as a quantity for ranking the snapshots generated in each cycle. By repeating a series of cycles for the selected top ranked snapshots, dissociation PaCS-MD (dPaCS-MD) generates structures with larger Inter-COM distances than those found in the previous cycle, which significantly enhances the probability of transitions from the bound to unbound states 39,48,49 . Short MD trajectories, a series of molecular configurations, connect the initial bound and final unbound states along the dissociation pathways, and the MD trajectories from many trials of dPaCS-MD can be combined to generate different dissociation pathways, which mutually overlap in conformational space.…”

Section: Introductionmentioning

confidence: 99%

Dissociation pathways of the p53 DNA binding domain from DNA and critical roles of key residues elucidated by dPaCS-MD/MSM

Sobeh

Kitao

2021

Preprint

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The dissociation process of the DNA binding domain of p53 (p53-DBD) from a DNA duplex that contains the consensus sequence, which is the specific target of p53-DBD, was investigated by a combination of dissociation parallel cascade selection molecular dynamics (dPaCS-MD) and the Markov state model (MSM). Based on an all-atom model including explicit solvent, we first simulated the p53-DBD dissociation processes by 75 trials of dPaCS-MD, which required an average simulation time of 11.2 ± 2.2 ns per trial. By setting the axis of the DNA duplex as the Z-axis and the binding side of p53-DBD on DNA as the + side of the X-axis, we found that dissociations took place along the +X and −Y directions (−Y directions) in 93% of the cases, while 7% of the cases moved along +X and +Y directions (+Y directions). Toward the −Y directions, p53-DBD dissociated first from the major groove and then detached from the minor groove, while unbinding from the minor groove occurred first in dissociations along the +Y directions. Analysis of the free energy landscape by MSM showed that loss of the minor groove interaction with p53-DBD toward the +Y directions incurred a relatively high energy cost (1.1 kcal/mol) upon a critical transition, whereas major groove detachment more frequently occurred with lower free energy costs. The standard binding free energy calculated from the free energy landscape was −10.9 ± 0.4 kcal/mol, which agrees with an experimental value of –11.1 kcal/mol. These results indicate that the dPaCS-MD/MSM combination can be a powerful tool to investigate dissociation mechanisms of two large molecules. Minor groove binding is mainly stabilized by R248, identified as the most important residue that tightly binds deep inside the minor groove. Analysis of the p53 key residues for DNA binding indicates high correlations with cancer-related mutations, confirming that impairment of the interactions between p53-DBD and DNA can be frequently related to cancer.

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Parallel Cascade Selection Molecular Dynamics Simulations for Transition Pathway Sampling of Biomolecules

Cited by 2 publications

References 45 publications

Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM

Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM

Dissociation pathways of the p53 DNA binding domain from DNA and critical roles of key residues elucidated by dPaCS-MD/MSM

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