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  Partial least squares functional mode analysis: Application to the membrane proteins AQP1, Aqy1 and CLC-ec1.

Krivobokova, T., Briones, R., Hub, J. S., Munk, A., & de Groot, B. L. (2012). Partial least squares functional mode analysis: Application to the membrane proteins AQP1, Aqy1 and CLC-ec1. Biophysical Journal, 103(4), 786-796. doi:10.1016/j.bpj.2012.07.022.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-C523-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-C77D-9
Genre: Journal Article

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Krivobokova, T., Author
Briones, R.1, Author              
Hub, J. S.1, Author              
Munk, A.2, Author              
de Groot, B. L.1, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              
2Research Group of Statistical Inverse-Problems in Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_1113580              

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 Abstract: We introduce an approach based on the recently introduced functional mode analysis to identify collective modes of internal dynamics that maximally correlate to an external order parameter of functional interest. Input structural data can be either experimentally determined structure ensembles or simulated ensembles, such as molecular dynamics trajectories. Partial least-squares regression is shown to yield a robust solution to the multidimensional optimization problem, with a minimal and controllable risk of overfitting, as shown by extensive cross-validation. Several examples illustrate that the partial least-squares-based functional mode analysis successfully reveals the collective dynamics underlying the fluctuations in selected functional order parameters. Applications to T4 lysozyme, the Trp-cage, the aquaporin channels Aqy1 and hAQP1, and the CLC-ec1 chloride antiporter are presented in which the active site geometry, the hydrophobic solvent-accessible surface, channel gating dynamics, water permeability (pf), and a dihedral angle are defined as functional order parameters. The Aqy1 case reveals a gating mechanism that connects the inner channel gating residues with the protein surface, thereby providing an explanation of how the membrane may affect the channel. hAQP1 shows how the pf correlates with structural changes around the aromatic/arginine region of the pore. The CLC-ec1 application shows how local motions of the gating Glu148 couple to a collective motion that affects ion affinity in the pore.

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Language(s): eng - English
 Dates: 20122012-08-22
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.bpj.2012.07.022
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Title: Biophysical Journal
Source Genre: Journal
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Pages: - Volume / Issue: 103 (4) Sequence Number: - Start / End Page: 786 - 796 Identifier: -