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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 drug-free and-bound CmABCB1.(A) Structure of CmABCB1. Two dimer chains are in orange and gray. Each of right and left subunits consists of TMD and NBD, where membrane spanning regions are colored in light brown. (B) Migration of rhodamine 6G center-of-mass along z-axis in 150-ns drug-bound simulation. Green and pink boxes correspond to simulation time ranges used for calculating Motion Trees in Fig 3D and Panel B in S3 Fig (C) Stable binding site including rhodamine 6G (cyan) and two phenylalanine side-chains of 138' and 384'. Colors of two dimer chains are same as those in (A). (D) Motion Trees calculated from last 50-ns trajectory of drug-free and-bound states. Nodes and corresponding structures are indicated with same colors, blue for larger and red for smaller portions. (E) Probability distribution of distance between center-of-masses of two subunits for drug-free (blue) and drug-bound (red) states. (F) Probability distribution of distance between center-of-masses of aromatic rings of Phe138 and Phe384 for left (cyan) and right (blue) subunits of the drug-free state, and for left (green) and right (red) subunits of the drug-bound state. (G) Probability distribution of RMSD for elbow-helix/TM1 relative to other TMD region from the crystal structure of the free form. Color scheme is same as that in (F).
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pone.0131583.g003: Motion Trees for drug-free and-bound CmABCB1.(A) Structure of CmABCB1. Two dimer chains are in orange and gray. Each of right and left subunits consists of TMD and NBD, where membrane spanning regions are colored in light brown. (B) Migration of rhodamine 6G center-of-mass along z-axis in 150-ns drug-bound simulation. Green and pink boxes correspond to simulation time ranges used for calculating Motion Trees in Fig 3D and Panel B in S3 Fig (C) Stable binding site including rhodamine 6G (cyan) and two phenylalanine side-chains of 138' and 384'. Colors of two dimer chains are same as those in (A). (D) Motion Trees calculated from last 50-ns trajectory of drug-free and-bound states. Nodes and corresponding structures are indicated with same colors, blue for larger and red for smaller portions. (E) Probability distribution of distance between center-of-masses of two subunits for drug-free (blue) and drug-bound (red) states. (F) Probability distribution of distance between center-of-masses of aromatic rings of Phe138 and Phe384 for left (cyan) and right (blue) subunits of the drug-free state, and for left (green) and right (red) subunits of the drug-bound state. (G) Probability distribution of RMSD for elbow-helix/TM1 relative to other TMD region from the crystal structure of the free form. Color scheme is same as that in (F).

Mentions: The ATP-binding cassette (ABC) multidrug transporter is an ATP-dependent efflux pump with a broad range of drug specificity. Drug transport occurs during the process of structural transformation from inward-open to outward-open structures driven by ATP binding and hydrolysis. Here, we chose a eukaryotic member of the ABC multidrug transporter family, CmABCB1, as the simulation system. CmABCB1 adopts a home-dimeric architecture with each subunit consisting of a nucleotide binding domain (NBD) that binds and hydrolyzes ATP to power the transport process and a transmembrane domain (TMD) that creates the translocation pathways for substrates (Fig 3A). Each TMD is composed of an N-terminal elbow helix (elbow H) followed by six transmembrane helices (TM1-6) and two short intracellular helices, of which TM4 and TM5 are swapped between the two TMDs, that is, six transmembrane helices of a TMD are TM1, TM2, TM3, TM4', TM5', TM6 (left TMD in Fig 3A), and the other are TM1', TM2', TM3', TM4, TM5 and TM6' (right TMD in Fig 3A), where “'” indicates the helix of another chain.


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 drug-free and-bound CmABCB1.(A) Structure of CmABCB1. Two dimer chains are in orange and gray. Each of right and left subunits consists of TMD and NBD, where membrane spanning regions are colored in light brown. (B) Migration of rhodamine 6G center-of-mass along z-axis in 150-ns drug-bound simulation. Green and pink boxes correspond to simulation time ranges used for calculating Motion Trees in Fig 3D and Panel B in S3 Fig (C) Stable binding site including rhodamine 6G (cyan) and two phenylalanine side-chains of 138' and 384'. Colors of two dimer chains are same as those in (A). (D) Motion Trees calculated from last 50-ns trajectory of drug-free and-bound states. Nodes and corresponding structures are indicated with same colors, blue for larger and red for smaller portions. (E) Probability distribution of distance between center-of-masses of two subunits for drug-free (blue) and drug-bound (red) states. (F) Probability distribution of distance between center-of-masses of aromatic rings of Phe138 and Phe384 for left (cyan) and right (blue) subunits of the drug-free state, and for left (green) and right (red) subunits of the drug-bound state. (G) Probability distribution of RMSD for elbow-helix/TM1 relative to other TMD region from the crystal structure of the free form. Color scheme is same as that in (F).
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Related In: Results  -  Collection

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pone.0131583.g003: Motion Trees for drug-free and-bound CmABCB1.(A) Structure of CmABCB1. Two dimer chains are in orange and gray. Each of right and left subunits consists of TMD and NBD, where membrane spanning regions are colored in light brown. (B) Migration of rhodamine 6G center-of-mass along z-axis in 150-ns drug-bound simulation. Green and pink boxes correspond to simulation time ranges used for calculating Motion Trees in Fig 3D and Panel B in S3 Fig (C) Stable binding site including rhodamine 6G (cyan) and two phenylalanine side-chains of 138' and 384'. Colors of two dimer chains are same as those in (A). (D) Motion Trees calculated from last 50-ns trajectory of drug-free and-bound states. Nodes and corresponding structures are indicated with same colors, blue for larger and red for smaller portions. (E) Probability distribution of distance between center-of-masses of two subunits for drug-free (blue) and drug-bound (red) states. (F) Probability distribution of distance between center-of-masses of aromatic rings of Phe138 and Phe384 for left (cyan) and right (blue) subunits of the drug-free state, and for left (green) and right (red) subunits of the drug-bound state. (G) Probability distribution of RMSD for elbow-helix/TM1 relative to other TMD region from the crystal structure of the free form. Color scheme is same as that in (F).
Mentions: The ATP-binding cassette (ABC) multidrug transporter is an ATP-dependent efflux pump with a broad range of drug specificity. Drug transport occurs during the process of structural transformation from inward-open to outward-open structures driven by ATP binding and hydrolysis. Here, we chose a eukaryotic member of the ABC multidrug transporter family, CmABCB1, as the simulation system. CmABCB1 adopts a home-dimeric architecture with each subunit consisting of a nucleotide binding domain (NBD) that binds and hydrolyzes ATP to power the transport process and a transmembrane domain (TMD) that creates the translocation pathways for substrates (Fig 3A). Each TMD is composed of an N-terminal elbow helix (elbow H) followed by six transmembrane helices (TM1-6) and two short intracellular helices, of which TM4 and TM5 are swapped between the two TMDs, that is, six transmembrane helices of a TMD are TM1, TM2, TM3, TM4', TM5', TM6 (left TMD in Fig 3A), and the other are TM1', TM2', TM3', TM4, TM5 and TM6' (right TMD in Fig 3A), where “'” indicates the helix of another chain.

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