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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.

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LSDMap of the coarse-grained DMC model of PYP.Structures with large positive first diffusion coordinate (DC1) are globular and similar to the pG state, while structures with large negative DC1 are almost fully extended. The intermediate region near DC1∼2.5 correspond to potential structures for further consideration as candidate signaling pB-state configurations. Figures S1, S2, and S3 in Text S1 show representative configurations from each region. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.
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pcbi-1003797-g001: LSDMap of the coarse-grained DMC model of PYP.Structures with large positive first diffusion coordinate (DC1) are globular and similar to the pG state, while structures with large negative DC1 are almost fully extended. The intermediate region near DC1∼2.5 correspond to potential structures for further consideration as candidate signaling pB-state configurations. Figures S1, S2, and S3 in Text S1 show representative configurations from each region. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.

Mentions: In Figure 1 the free energy is shown in terms of the first and third DCs. The slowest collective motion of this DMC system corresponds to a global unfolding of the protein. Structures with a large positive DC1 correspond to configurations very similar to the pG native state, while configurations with a large negative DC1 are unfolded. The figure shows an additional minimum in the intermediate region of the free energy, and configurations within this minimum are good candidate pB-state configurations. Representative structures from each region are presented in Figures S1, S2, and S3 in Text S1. In addition, histograms of the Cα RMSD to the NMR pG structure are shown in Figure S4 in Text S1. Approximately 1000 coarse-grained structures were collected from the local minimum in free energy near DC1 = 2.5 for further analysis. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.


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)

LSDMap of the coarse-grained DMC model of PYP.Structures with large positive first diffusion coordinate (DC1) are globular and similar to the pG state, while structures with large negative DC1 are almost fully extended. The intermediate region near DC1∼2.5 correspond to potential structures for further consideration as candidate signaling pB-state configurations. Figures S1, S2, and S3 in Text S1 show representative configurations from each region. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003797-g001: LSDMap of the coarse-grained DMC model of PYP.Structures with large positive first diffusion coordinate (DC1) are globular and similar to the pG state, while structures with large negative DC1 are almost fully extended. The intermediate region near DC1∼2.5 correspond to potential structures for further consideration as candidate signaling pB-state configurations. Figures S1, S2, and S3 in Text S1 show representative configurations from each region. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.
Mentions: In Figure 1 the free energy is shown in terms of the first and third DCs. The slowest collective motion of this DMC system corresponds to a global unfolding of the protein. Structures with a large positive DC1 correspond to configurations very similar to the pG native state, while configurations with a large negative DC1 are unfolded. The figure shows an additional minimum in the intermediate region of the free energy, and configurations within this minimum are good candidate pB-state configurations. Representative structures from each region are presented in Figures S1, S2, and S3 in Text S1. In addition, histograms of the Cα RMSD to the NMR pG structure are shown in Figure S4 in Text S1. Approximately 1000 coarse-grained structures were collected from the local minimum in free energy near DC1 = 2.5 for further analysis. The free energy is shown in terms of DC1 and DC3 to allow for a clearer view of the intermediate region.

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