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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 tree for substrate-free ADK.(A) Motion Tree constructed from 50-ns dynamics of substrate-free adenylate kinase. Five nodes are shown with corresponding parts of ADK structure in blue (larger domain) and red (smaller domain). (B) RMSF value for smaller (red) domain after fitting to corresponding larger domain is plotted at each node as a function of MT score. Dotted line is least square fit with zero at origin.
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pone.0131583.g001: Motion tree for substrate-free ADK.(A) Motion Tree constructed from 50-ns dynamics of substrate-free adenylate kinase. Five nodes are shown with corresponding parts of ADK structure in blue (larger domain) and red (smaller domain). (B) RMSF value for smaller (red) domain after fitting to corresponding larger domain is plotted at each node as a function of MT score. Dotted line is least square fit with zero at origin.

Mentions: Fig 1A shows an illustrative example of a Motion Tree constructed from the 50-ns MD simulation of adenylate kinase (ADK) in the ligand-free state. ADK has two lids to bind ATP and AMP, which undergo structural changes to the closed form on ligand binding. The Motion Tree is interpreted by going down from the root to the leaves as follows: The root denotes the largest cluster composed of all residues in ADK, and is divided at node 1 into two sub-clusters, the first corresponding to the ATP-lid (residue 123–158) and the second composed of the AMP-lid and the core domain. The height from the bottom of the tree (MT score at node 1; s1) is the largest (s1 = 5.7 Å), indicating that the fluctuation between the ATP-lid and the AMP-lid/core domain is the largest in ADK dynamics, and that the fluctuations occurring within the two sub-clusters are smaller than s1. Node 1 describes the inter-domain motion between the ATP-lid and the AMP-lid/core domain in terms of protein dynamics. However, these domains are not completely rigid bodies but contain intra-domain motions, which are represented by descendant nodes in the tree. Node 2 thus exhibits the largest motion within the AMP-lid/core domain. The intra-domain motion at node 2 can be interpreted as inter-domain motion between the AMP-lid and the core domain since the node separates the AMP-lid/core domain further into the AMP-lid (residue 31–77) and the core domain. The MT score s2 (= 3.3 Å) is smaller than s1, i.e., the fluctuation between the AMP-lid and the core domain is smaller in amplitude than that between the ATP-lid and the AMP-lid/core domain. Nodes 3 to 5 denote the intra-domain fluctuations in the three domains, the ATP-lid, AMP-lid, and the core domain, which are further divided into sub-clusters. Their MT scores are less than half of s1 and s2 (s3 = 1.6, s4 = 1.5 and s5 = 1.4 Å) and indicate the dominance of the two largest inter-domain motions in ADK dynamics.


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 tree for substrate-free ADK.(A) Motion Tree constructed from 50-ns dynamics of substrate-free adenylate kinase. Five nodes are shown with corresponding parts of ADK structure in blue (larger domain) and red (smaller domain). (B) RMSF value for smaller (red) domain after fitting to corresponding larger domain is plotted at each node as a function of MT score. Dotted line is least square fit with zero at origin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492737&req=5

pone.0131583.g001: Motion tree for substrate-free ADK.(A) Motion Tree constructed from 50-ns dynamics of substrate-free adenylate kinase. Five nodes are shown with corresponding parts of ADK structure in blue (larger domain) and red (smaller domain). (B) RMSF value for smaller (red) domain after fitting to corresponding larger domain is plotted at each node as a function of MT score. Dotted line is least square fit with zero at origin.
Mentions: Fig 1A shows an illustrative example of a Motion Tree constructed from the 50-ns MD simulation of adenylate kinase (ADK) in the ligand-free state. ADK has two lids to bind ATP and AMP, which undergo structural changes to the closed form on ligand binding. The Motion Tree is interpreted by going down from the root to the leaves as follows: The root denotes the largest cluster composed of all residues in ADK, and is divided at node 1 into two sub-clusters, the first corresponding to the ATP-lid (residue 123–158) and the second composed of the AMP-lid and the core domain. The height from the bottom of the tree (MT score at node 1; s1) is the largest (s1 = 5.7 Å), indicating that the fluctuation between the ATP-lid and the AMP-lid/core domain is the largest in ADK dynamics, and that the fluctuations occurring within the two sub-clusters are smaller than s1. Node 1 describes the inter-domain motion between the ATP-lid and the AMP-lid/core domain in terms of protein dynamics. However, these domains are not completely rigid bodies but contain intra-domain motions, which are represented by descendant nodes in the tree. Node 2 thus exhibits the largest motion within the AMP-lid/core domain. The intra-domain motion at node 2 can be interpreted as inter-domain motion between the AMP-lid and the core domain since the node separates the AMP-lid/core domain further into the AMP-lid (residue 31–77) and the core domain. The MT score s2 (= 3.3 Å) is smaller than s1, i.e., the fluctuation between the AMP-lid and the core domain is smaller in amplitude than that between the ATP-lid and the AMP-lid/core domain. Nodes 3 to 5 denote the intra-domain fluctuations in the three domains, the ATP-lid, AMP-lid, and the core domain, which are further divided into sub-clusters. Their MT scores are less than half of s1 and s2 (s3 = 1.6, s4 = 1.5 and s5 = 1.4 Å) and indicate the dominance of the two largest inter-domain motions in ADK dynamics.

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