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A correspondence between solution-state dynamics of an individual protein and the sequence and conformational diversity of its family.

Friedland GD, Lakomek NA, Griesinger C, Meiler J, Kortemme T - PLoS Comput. Biol. (2009)

Bottom Line: We show that the Backrub motional mechanism can simultaneously explore protein native-state dynamics measured by RDCs, encompass the conformational variability present in ubiquitin complex structures and facilitate sampling of conformational and sequence variability matching those occurring in the ubiquitin protein family.Our results thus support an overall relation between protein dynamics and conformational changes enabling sequence changes in evolution.More practically, the presented method can be applied to improve protein design predictions by accounting for intrinsic native-state dynamics.

View Article: PubMed Central - PubMed

Affiliation: Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Conformational ensembles are increasingly recognized as a useful representation to describe fundamental relationships between protein structure, dynamics and function. Here we present an ensemble of ubiquitin in solution that is created by sampling conformational space without experimental information using "Backrub" motions inspired by alternative conformations observed in sub-Angstrom resolution crystal structures. Backrub-generated structures are then selected to produce an ensemble that optimizes agreement with nuclear magnetic resonance (NMR) Residual Dipolar Couplings (RDCs). Using this ensemble, we probe two proposed relationships between properties of protein ensembles: (i) a link between native-state dynamics and the conformational heterogeneity observed in crystal structures, and (ii) a relation between dynamics of an individual protein and the conformational variability explored by its natural family. We show that the Backrub motional mechanism can simultaneously explore protein native-state dynamics measured by RDCs, encompass the conformational variability present in ubiquitin complex structures and facilitate sampling of conformational and sequence variability matching those occurring in the ubiquitin protein family. Our results thus support an overall relation between protein dynamics and conformational changes enabling sequence changes in evolution. More practically, the presented method can be applied to improve protein design predictions by accounting for intrinsic native-state dynamics.

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Sampling of sequence space by computational design on different ubiquitin ensembles.(A) Designed sequences on non-RDC-optimized (light blue), and RDC-optimized (dark blue) Backrub ensembles of maximum segment length of 12 with kT = 1.2. (B) and (C): Low-scoring designed sequences on the fixed backbone of the X-ray structure 1UBQ (orange); on non-RDC-optimized Backrub ensembles with maximum segment length of 12 with kT = 0.3 (green), kT = 1.2 (blue), and kT = 4.8 (cyan); and (B) low-scoring designed sequences on the ubiquitin X-ray ensemble (red), or (C) sequences from the UBQ subfamily (brown). (Note that the dimensions shown in the plots are selected to maximize the variation of the points in each plot and will differ between plots).
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pcbi-1000393-g006: Sampling of sequence space by computational design on different ubiquitin ensembles.(A) Designed sequences on non-RDC-optimized (light blue), and RDC-optimized (dark blue) Backrub ensembles of maximum segment length of 12 with kT = 1.2. (B) and (C): Low-scoring designed sequences on the fixed backbone of the X-ray structure 1UBQ (orange); on non-RDC-optimized Backrub ensembles with maximum segment length of 12 with kT = 0.3 (green), kT = 1.2 (blue), and kT = 4.8 (cyan); and (B) low-scoring designed sequences on the ubiquitin X-ray ensemble (red), or (C) sequences from the UBQ subfamily (brown). (Note that the dimensions shown in the plots are selected to maximize the variation of the points in each plot and will differ between plots).

Mentions: The sequence spaces sampled by the RDC-optimized and non-RDC-optimized Backrub ensembles with optimal Backrub parameters (maximum segment length of 12 and kT = 1.2) are very similar (Figure 6A). This is consistent with the idea that the Backrub method captures a significant portion of near-native protein motions, even without directly incorporating the RDC information into the model. In the following, we use results for non-RDC-optimized ensembles; the results are similar for RDC-optimized ensembles.


A correspondence between solution-state dynamics of an individual protein and the sequence and conformational diversity of its family.

Friedland GD, Lakomek NA, Griesinger C, Meiler J, Kortemme T - PLoS Comput. Biol. (2009)

Sampling of sequence space by computational design on different ubiquitin ensembles.(A) Designed sequences on non-RDC-optimized (light blue), and RDC-optimized (dark blue) Backrub ensembles of maximum segment length of 12 with kT = 1.2. (B) and (C): Low-scoring designed sequences on the fixed backbone of the X-ray structure 1UBQ (orange); on non-RDC-optimized Backrub ensembles with maximum segment length of 12 with kT = 0.3 (green), kT = 1.2 (blue), and kT = 4.8 (cyan); and (B) low-scoring designed sequences on the ubiquitin X-ray ensemble (red), or (C) sequences from the UBQ subfamily (brown). (Note that the dimensions shown in the plots are selected to maximize the variation of the points in each plot and will differ between plots).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682763&req=5

pcbi-1000393-g006: Sampling of sequence space by computational design on different ubiquitin ensembles.(A) Designed sequences on non-RDC-optimized (light blue), and RDC-optimized (dark blue) Backrub ensembles of maximum segment length of 12 with kT = 1.2. (B) and (C): Low-scoring designed sequences on the fixed backbone of the X-ray structure 1UBQ (orange); on non-RDC-optimized Backrub ensembles with maximum segment length of 12 with kT = 0.3 (green), kT = 1.2 (blue), and kT = 4.8 (cyan); and (B) low-scoring designed sequences on the ubiquitin X-ray ensemble (red), or (C) sequences from the UBQ subfamily (brown). (Note that the dimensions shown in the plots are selected to maximize the variation of the points in each plot and will differ between plots).
Mentions: The sequence spaces sampled by the RDC-optimized and non-RDC-optimized Backrub ensembles with optimal Backrub parameters (maximum segment length of 12 and kT = 1.2) are very similar (Figure 6A). This is consistent with the idea that the Backrub method captures a significant portion of near-native protein motions, even without directly incorporating the RDC information into the model. In the following, we use results for non-RDC-optimized ensembles; the results are similar for RDC-optimized ensembles.

Bottom Line: We show that the Backrub motional mechanism can simultaneously explore protein native-state dynamics measured by RDCs, encompass the conformational variability present in ubiquitin complex structures and facilitate sampling of conformational and sequence variability matching those occurring in the ubiquitin protein family.Our results thus support an overall relation between protein dynamics and conformational changes enabling sequence changes in evolution.More practically, the presented method can be applied to improve protein design predictions by accounting for intrinsic native-state dynamics.

View Article: PubMed Central - PubMed

Affiliation: Graduate Group in Biophysics, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Conformational ensembles are increasingly recognized as a useful representation to describe fundamental relationships between protein structure, dynamics and function. Here we present an ensemble of ubiquitin in solution that is created by sampling conformational space without experimental information using "Backrub" motions inspired by alternative conformations observed in sub-Angstrom resolution crystal structures. Backrub-generated structures are then selected to produce an ensemble that optimizes agreement with nuclear magnetic resonance (NMR) Residual Dipolar Couplings (RDCs). Using this ensemble, we probe two proposed relationships between properties of protein ensembles: (i) a link between native-state dynamics and the conformational heterogeneity observed in crystal structures, and (ii) a relation between dynamics of an individual protein and the conformational variability explored by its natural family. We show that the Backrub motional mechanism can simultaneously explore protein native-state dynamics measured by RDCs, encompass the conformational variability present in ubiquitin complex structures and facilitate sampling of conformational and sequence variability matching those occurring in the ubiquitin protein family. Our results thus support an overall relation between protein dynamics and conformational changes enabling sequence changes in evolution. More practically, the presented method can be applied to improve protein design predictions by accounting for intrinsic native-state dynamics.

Show MeSH