Limits...
Multiscale approach to the determination of the photoactive yellow protein signaling state ensemble.

A Rohrdanz M, Zheng W, Lambeth B, Vreede J, Clementi C - PLoS Comput. Biol. (2014)

Bottom Line: The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret.We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented.This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America; Chemistry Department, Rice University, Houston, Texas, United States of America.

ABSTRACT
The nature of the optical cycle of photoactive yellow protein (PYP) makes its elucidation challenging for both experiment and theory. The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret. Here, through an innovative combination of computational methods, a prediction and analysis of the biological signaling state of PYP is presented. Coarse-grained modeling and locally scaled diffusion map are first used to obtain a rough bird's-eye view of the free energy landscape of photo-activated PYP. Then all-atom reconstruction, followed by an enhanced sampling scheme; diffusion map-directed-molecular dynamics are used to focus in on the signaling-state region of configuration space and obtain an ensemble of signaling state structures. To the best of our knowledge, this is the first time an all-atom reconstruction from a coarse grained model has been performed in a relatively unexplored region of molecular configuration space. We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented. This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical.

Show MeSH
Diffusion Map-directed-Molecular Dynamics (DM-d-MD) and molecular dynamics (MD) results.The initial starting configuration for the DM-d-MD is denoted by the gold circle. The DM-d-MD frontier points are shown in pink, and the minimum-energy frontier point is denoted by a gold star. The MD results from approximately 100 trajectories initiated from the minimum-energy DM-d-MD frontier point are shown in light blue. For reference, the coordinates for the experimental Δ25 (PDB ID 1XFQ) structures are shown as dark blue *, and the experimental WT-PYP (PDB ID: 2KX6) structures as red *. The underlying grey contours are those from Figure 1 of reference [34].
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4214557&req=5

pcbi-1003797-g002: Diffusion Map-directed-Molecular Dynamics (DM-d-MD) and molecular dynamics (MD) results.The initial starting configuration for the DM-d-MD is denoted by the gold circle. The DM-d-MD frontier points are shown in pink, and the minimum-energy frontier point is denoted by a gold star. The MD results from approximately 100 trajectories initiated from the minimum-energy DM-d-MD frontier point are shown in light blue. For reference, the coordinates for the experimental Δ25 (PDB ID 1XFQ) structures are shown as dark blue *, and the experimental WT-PYP (PDB ID: 2KX6) structures as red *. The underlying grey contours are those from Figure 1 of reference [34].

Mentions: To explore the molecular configuration space around these solvated structures, DM-d-MD [52] is initiated from each equilibrated structure. Previous work has suggested two collective variables: the root mean square deviation (RMSD) of the α3 helix (residues 41–53) with respect to an ideal helix, and the distance between the GLU46 residue and the pCA chromophore, are good collective variables in which to visualize the system, and that there are a few metastable states in between the pB and pG configurations [34]. These coordinates are used in Figure 2, along with the underlying black free energy contours obtained from previous parallel tempering calculations (See Figure 1 from Vreede, et al. [34]).


Multiscale approach to the determination of the photoactive yellow protein signaling state ensemble.

A Rohrdanz M, Zheng W, Lambeth B, Vreede J, Clementi C - PLoS Comput. Biol. (2014)

Diffusion Map-directed-Molecular Dynamics (DM-d-MD) and molecular dynamics (MD) results.The initial starting configuration for the DM-d-MD is denoted by the gold circle. The DM-d-MD frontier points are shown in pink, and the minimum-energy frontier point is denoted by a gold star. The MD results from approximately 100 trajectories initiated from the minimum-energy DM-d-MD frontier point are shown in light blue. For reference, the coordinates for the experimental Δ25 (PDB ID 1XFQ) structures are shown as dark blue *, and the experimental WT-PYP (PDB ID: 2KX6) structures as red *. The underlying grey contours are those from Figure 1 of reference [34].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214557&req=5

pcbi-1003797-g002: Diffusion Map-directed-Molecular Dynamics (DM-d-MD) and molecular dynamics (MD) results.The initial starting configuration for the DM-d-MD is denoted by the gold circle. The DM-d-MD frontier points are shown in pink, and the minimum-energy frontier point is denoted by a gold star. The MD results from approximately 100 trajectories initiated from the minimum-energy DM-d-MD frontier point are shown in light blue. For reference, the coordinates for the experimental Δ25 (PDB ID 1XFQ) structures are shown as dark blue *, and the experimental WT-PYP (PDB ID: 2KX6) structures as red *. The underlying grey contours are those from Figure 1 of reference [34].
Mentions: To explore the molecular configuration space around these solvated structures, DM-d-MD [52] is initiated from each equilibrated structure. Previous work has suggested two collective variables: the root mean square deviation (RMSD) of the α3 helix (residues 41–53) with respect to an ideal helix, and the distance between the GLU46 residue and the pCA chromophore, are good collective variables in which to visualize the system, and that there are a few metastable states in between the pB and pG configurations [34]. These coordinates are used in Figure 2, along with the underlying black free energy contours obtained from previous parallel tempering calculations (See Figure 1 from Vreede, et al. [34]).

Bottom Line: The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret.We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented.This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas, United States of America; Chemistry Department, Rice University, Houston, Texas, United States of America.

ABSTRACT
The nature of the optical cycle of photoactive yellow protein (PYP) makes its elucidation challenging for both experiment and theory. The long transition times render conventional simulation methods ineffective, and yet the short signaling-state lifetime makes experimental data difficult to obtain and interpret. Here, through an innovative combination of computational methods, a prediction and analysis of the biological signaling state of PYP is presented. Coarse-grained modeling and locally scaled diffusion map are first used to obtain a rough bird's-eye view of the free energy landscape of photo-activated PYP. Then all-atom reconstruction, followed by an enhanced sampling scheme; diffusion map-directed-molecular dynamics are used to focus in on the signaling-state region of configuration space and obtain an ensemble of signaling state structures. To the best of our knowledge, this is the first time an all-atom reconstruction from a coarse grained model has been performed in a relatively unexplored region of molecular configuration space. We compare our signaling state prediction with previous computational and more recent experimental results, and the comparison is favorable, which validates the method presented. This approach provides additional insight to understand the PYP photo cycle, and can be applied to other systems for which more direct methods are impractical.

Show MeSH