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Motion Tree Delineates Hierarchical Structure of Protein Dynamics Observed in Molecular Dynamics Simulation.

Moritsugu K, Koike R, Yamada K, Kato H, Kidera A - PLoS ONE (2015)

Bottom Line: A straightforward and intuitive analysis of protein dynamics observed in MD simulation trajectories is therefore of growing significance with the large increase in both the simulation time and system size.The comparison of two Motion Trees calculated from MD simulations of ligand-free and -bound glutamine binding proteins clarified changes in inherent dynamics upon ligand binding appeared in both large domains and a small loop that stabilized ligand molecule.These applications demonstrated the capabilities of Motion Trees to provide an at-a-glance view of various sizes of functional motions inherent in the complicated MD trajectory.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.

ABSTRACT
Molecular dynamics (MD) simulations of proteins provide important information to understand their functional mechanisms, which are, however, likely to be hidden behind their complicated motions with a wide range of spatial and temporal scales. A straightforward and intuitive analysis of protein dynamics observed in MD simulation trajectories is therefore of growing significance with the large increase in both the simulation time and system size. In this study, we propose a novel description of protein motions based on the hierarchical clustering of fluctuations in the inter-atomic distances calculated from an MD trajectory, which constructs a single tree diagram, named a "Motion Tree", to determine a set of rigid-domain pairs hierarchically along with associated inter-domain fluctuations. The method was first applied to the MD trajectory of substrate-free adenylate kinase to clarify the usefulness of the Motion Tree, which illustrated a clear-cut dynamics picture of the inter-domain motions involving the ATP/AMP lid and the core domain together with the associated amplitudes and correlations. The comparison of two Motion Trees calculated from MD simulations of ligand-free and -bound glutamine binding proteins clarified changes in inherent dynamics upon ligand binding appeared in both large domains and a small loop that stabilized ligand molecule. Another application to a huge protein, a multidrug ATP binding cassette (ABC) transporter, captured significant increases of fluctuations upon binding a drug molecule observed in both large scale inter-subunit motions and a motion localized at a transmembrane helix, which may be a trigger to the subsequent structural change from inward-open to outward-open states to transport the drug molecule. These applications demonstrated the capabilities of Motion Trees to provide an at-a-glance view of various sizes of functional motions inherent in the complicated MD trajectory.

No MeSH data available.


Related in: MedlinePlus

Motion trees for ligand-free and ligand-bound GBP.(A) Motion Trees constructed from 50-ns trajectories of ligand-free and ligand-bound GBP, where flexible C-terminuses (residues 222–226) were ignored. Three nodes are shown with corresponding parts of GBP structures in blue (larger domain) and red (smaller domain). Node numbers for ligand-bound form are given so that they have same structural assignments as those for ligand-free form. MT score at each node is given in parenthesis. Four moving elements identified are two domains, L1 (residue 5–10, 28–89, 183–224 (free) and 5–16, 27–82, 187–224 (bound)) and L2 (90–97, 108–182 (free) and 83–95, 106–186 (bound)), and two loops, S1 (11–27 (free) and 17–26 (bound)) and S2 (98–107 (free) and 96–105 (bound)). (B) Center-of-mass distances between L1 and L2, and (C) distances between nearest polar atoms belonging to Asp100 and Lys 110 in S2. Red plots are for free states and blue plots are for bound states. Values in crystal structures are also shown for free form (magenta) and bound form (cyan). (D) Simulated structures of S2 at 50 ns for free (red) and bound (blue) forms. Ion pair between side chains of Asp100 and Lys 110 is indicated by dotted line. (E) Simulated structures of S1 at 50 ns for free (red) and bound (blue) forms. The structures near S1 loop are also indicated by pink (free) and cyan (bound), as well as bound glutamine and side chains of Phe 13 and 50. (F) and (G) show RMSD values of residues 11–16 and 17–26 after fitting L1 to that of ligand-bound form of the crystal structure. Color scheme is same as that in (B) and (C).
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pone.0131583.g002: Motion trees for ligand-free and ligand-bound GBP.(A) Motion Trees constructed from 50-ns trajectories of ligand-free and ligand-bound GBP, where flexible C-terminuses (residues 222–226) were ignored. Three nodes are shown with corresponding parts of GBP structures in blue (larger domain) and red (smaller domain). Node numbers for ligand-bound form are given so that they have same structural assignments as those for ligand-free form. MT score at each node is given in parenthesis. Four moving elements identified are two domains, L1 (residue 5–10, 28–89, 183–224 (free) and 5–16, 27–82, 187–224 (bound)) and L2 (90–97, 108–182 (free) and 83–95, 106–186 (bound)), and two loops, S1 (11–27 (free) and 17–26 (bound)) and S2 (98–107 (free) and 96–105 (bound)). (B) Center-of-mass distances between L1 and L2, and (C) distances between nearest polar atoms belonging to Asp100 and Lys 110 in S2. Red plots are for free states and blue plots are for bound states. Values in crystal structures are also shown for free form (magenta) and bound form (cyan). (D) Simulated structures of S2 at 50 ns for free (red) and bound (blue) forms. Ion pair between side chains of Asp100 and Lys 110 is indicated by dotted line. (E) Simulated structures of S1 at 50 ns for free (red) and bound (blue) forms. The structures near S1 loop are also indicated by pink (free) and cyan (bound), as well as bound glutamine and side chains of Phe 13 and 50. (F) and (G) show RMSD values of residues 11–16 and 17–26 after fitting L1 to that of ligand-bound form of the crystal structure. Color scheme is same as that in (B) and (C).

Mentions: Fig 2A shows the Motion Trees derived, each of which successfully provides a complete picture depicting both large domain motions and local motions in a single tree diagram. These trees indicate that two large domains, L1 and L2, and two small loops, S1 and S2, contributes significantly to the GBP dynamics, although their MT scores, or the heights of the trees, greatly differ from each other, indicating changes in domain fluctuations on ligand binding. The comparison demonstrates that ligand binding reduces the amplitude of domain motions between L1 and L2 by more than three times ([s2 of free]/[s2 of bound] = 3.7 Å/1.1 Å). Dynamical stiffening seen in the Motion Trees is consistent with the MD trajectories. Fig 2B shows large difference in the distance (dCOM) fluctuation between the centers-of-mass of L1 and L2. Reduction in the amplitude can also be seen in the loop motions. A five times decrease can be found in the S2 loop ([s1 of free]/[s1 of bound] = 6.5 Å/1.3 Å). However, this change in dynamics was found to be mostly due to the side-chain polar contact between Asp100 and Lys 110; the bound state had contact for about half the simulation time, whereas this was broken to largely fluctuate S2 in the free form (Fig 2C and 2D). This change simply originated from the difference between the two crystal packing structures used in the MD simulations as the initial structures (Panel A in S2 Fig), and was probably irrelevant to ligand binding.


Motion Tree Delineates Hierarchical Structure of Protein Dynamics Observed in Molecular Dynamics Simulation.

Moritsugu K, Koike R, Yamada K, Kato H, Kidera A - PLoS ONE (2015)

Motion trees for ligand-free and ligand-bound GBP.(A) Motion Trees constructed from 50-ns trajectories of ligand-free and ligand-bound GBP, where flexible C-terminuses (residues 222–226) were ignored. Three nodes are shown with corresponding parts of GBP structures in blue (larger domain) and red (smaller domain). Node numbers for ligand-bound form are given so that they have same structural assignments as those for ligand-free form. MT score at each node is given in parenthesis. Four moving elements identified are two domains, L1 (residue 5–10, 28–89, 183–224 (free) and 5–16, 27–82, 187–224 (bound)) and L2 (90–97, 108–182 (free) and 83–95, 106–186 (bound)), and two loops, S1 (11–27 (free) and 17–26 (bound)) and S2 (98–107 (free) and 96–105 (bound)). (B) Center-of-mass distances between L1 and L2, and (C) distances between nearest polar atoms belonging to Asp100 and Lys 110 in S2. Red plots are for free states and blue plots are for bound states. Values in crystal structures are also shown for free form (magenta) and bound form (cyan). (D) Simulated structures of S2 at 50 ns for free (red) and bound (blue) forms. Ion pair between side chains of Asp100 and Lys 110 is indicated by dotted line. (E) Simulated structures of S1 at 50 ns for free (red) and bound (blue) forms. The structures near S1 loop are also indicated by pink (free) and cyan (bound), as well as bound glutamine and side chains of Phe 13 and 50. (F) and (G) show RMSD values of residues 11–16 and 17–26 after fitting L1 to that of ligand-bound form of the crystal structure. Color scheme is same as that in (B) and (C).
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Related In: Results  -  Collection

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pone.0131583.g002: Motion trees for ligand-free and ligand-bound GBP.(A) Motion Trees constructed from 50-ns trajectories of ligand-free and ligand-bound GBP, where flexible C-terminuses (residues 222–226) were ignored. Three nodes are shown with corresponding parts of GBP structures in blue (larger domain) and red (smaller domain). Node numbers for ligand-bound form are given so that they have same structural assignments as those for ligand-free form. MT score at each node is given in parenthesis. Four moving elements identified are two domains, L1 (residue 5–10, 28–89, 183–224 (free) and 5–16, 27–82, 187–224 (bound)) and L2 (90–97, 108–182 (free) and 83–95, 106–186 (bound)), and two loops, S1 (11–27 (free) and 17–26 (bound)) and S2 (98–107 (free) and 96–105 (bound)). (B) Center-of-mass distances between L1 and L2, and (C) distances between nearest polar atoms belonging to Asp100 and Lys 110 in S2. Red plots are for free states and blue plots are for bound states. Values in crystal structures are also shown for free form (magenta) and bound form (cyan). (D) Simulated structures of S2 at 50 ns for free (red) and bound (blue) forms. Ion pair between side chains of Asp100 and Lys 110 is indicated by dotted line. (E) Simulated structures of S1 at 50 ns for free (red) and bound (blue) forms. The structures near S1 loop are also indicated by pink (free) and cyan (bound), as well as bound glutamine and side chains of Phe 13 and 50. (F) and (G) show RMSD values of residues 11–16 and 17–26 after fitting L1 to that of ligand-bound form of the crystal structure. Color scheme is same as that in (B) and (C).
Mentions: Fig 2A shows the Motion Trees derived, each of which successfully provides a complete picture depicting both large domain motions and local motions in a single tree diagram. These trees indicate that two large domains, L1 and L2, and two small loops, S1 and S2, contributes significantly to the GBP dynamics, although their MT scores, or the heights of the trees, greatly differ from each other, indicating changes in domain fluctuations on ligand binding. The comparison demonstrates that ligand binding reduces the amplitude of domain motions between L1 and L2 by more than three times ([s2 of free]/[s2 of bound] = 3.7 Å/1.1 Å). Dynamical stiffening seen in the Motion Trees is consistent with the MD trajectories. Fig 2B shows large difference in the distance (dCOM) fluctuation between the centers-of-mass of L1 and L2. Reduction in the amplitude can also be seen in the loop motions. A five times decrease can be found in the S2 loop ([s1 of free]/[s1 of bound] = 6.5 Å/1.3 Å). However, this change in dynamics was found to be mostly due to the side-chain polar contact between Asp100 and Lys 110; the bound state had contact for about half the simulation time, whereas this was broken to largely fluctuate S2 in the free form (Fig 2C and 2D). This change simply originated from the difference between the two crystal packing structures used in the MD simulations as the initial structures (Panel A in S2 Fig), and was probably irrelevant to ligand binding.

Bottom Line: A straightforward and intuitive analysis of protein dynamics observed in MD simulation trajectories is therefore of growing significance with the large increase in both the simulation time and system size.The comparison of two Motion Trees calculated from MD simulations of ligand-free and -bound glutamine binding proteins clarified changes in inherent dynamics upon ligand binding appeared in both large domains and a small loop that stabilized ligand molecule.These applications demonstrated the capabilities of Motion Trees to provide an at-a-glance view of various sizes of functional motions inherent in the complicated MD trajectory.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Japan.

ABSTRACT
Molecular dynamics (MD) simulations of proteins provide important information to understand their functional mechanisms, which are, however, likely to be hidden behind their complicated motions with a wide range of spatial and temporal scales. A straightforward and intuitive analysis of protein dynamics observed in MD simulation trajectories is therefore of growing significance with the large increase in both the simulation time and system size. In this study, we propose a novel description of protein motions based on the hierarchical clustering of fluctuations in the inter-atomic distances calculated from an MD trajectory, which constructs a single tree diagram, named a "Motion Tree", to determine a set of rigid-domain pairs hierarchically along with associated inter-domain fluctuations. The method was first applied to the MD trajectory of substrate-free adenylate kinase to clarify the usefulness of the Motion Tree, which illustrated a clear-cut dynamics picture of the inter-domain motions involving the ATP/AMP lid and the core domain together with the associated amplitudes and correlations. The comparison of two Motion Trees calculated from MD simulations of ligand-free and -bound glutamine binding proteins clarified changes in inherent dynamics upon ligand binding appeared in both large domains and a small loop that stabilized ligand molecule. Another application to a huge protein, a multidrug ATP binding cassette (ABC) transporter, captured significant increases of fluctuations upon binding a drug molecule observed in both large scale inter-subunit motions and a motion localized at a transmembrane helix, which may be a trigger to the subsequent structural change from inward-open to outward-open states to transport the drug molecule. These applications demonstrated the capabilities of Motion Trees to provide an at-a-glance view of various sizes of functional motions inherent in the complicated MD trajectory.

No MeSH data available.


Related in: MedlinePlus