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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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Flexibility of different ubiquitin ensembles.(A) Structures of the C-alpha backbone traces of a RDC-optimized 50-member ensemble of maximum segment length of 12 with kT = 1.2. (B and D) Mean C-alpha difference distance values of indicated ensembles mapped onto the 1UBQ X-ray structure. (C) Theoretical B-factors from a Gaussian Network Model. Color coding for B, C and D: Green: 0–25% of the max value in the non-loop regions; Yellow: 25–50% of the max; Orange: 50–75% of the max; Red: 75–100% of the max; Grey: loop regions that were not included in the fit to the RDC measurements.
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pcbi-1000393-g004: Flexibility of different ubiquitin ensembles.(A) Structures of the C-alpha backbone traces of a RDC-optimized 50-member ensemble of maximum segment length of 12 with kT = 1.2. (B and D) Mean C-alpha difference distance values of indicated ensembles mapped onto the 1UBQ X-ray structure. (C) Theoretical B-factors from a Gaussian Network Model. Color coding for B, C and D: Green: 0–25% of the max value in the non-loop regions; Yellow: 25–50% of the max; Orange: 50–75% of the max; Red: 75–100% of the max; Grey: loop regions that were not included in the fit to the RDC measurements.

Mentions: The structural variability of the ensemble is illustrated in Figure 4A. The average NH order parameter in regular secondary structure elements is 0.76, the same as that computed for the model free analysis (0.77) described in Lakomek et al., but lower than that computed for the EROS ensemble (0.83) [4],[35].


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)

Flexibility of different ubiquitin ensembles.(A) Structures of the C-alpha backbone traces of a RDC-optimized 50-member ensemble of maximum segment length of 12 with kT = 1.2. (B and D) Mean C-alpha difference distance values of indicated ensembles mapped onto the 1UBQ X-ray structure. (C) Theoretical B-factors from a Gaussian Network Model. Color coding for B, C and D: Green: 0–25% of the max value in the non-loop regions; Yellow: 25–50% of the max; Orange: 50–75% of the max; Red: 75–100% of the max; Grey: loop regions that were not included in the fit to the RDC measurements.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682763&req=5

pcbi-1000393-g004: Flexibility of different ubiquitin ensembles.(A) Structures of the C-alpha backbone traces of a RDC-optimized 50-member ensemble of maximum segment length of 12 with kT = 1.2. (B and D) Mean C-alpha difference distance values of indicated ensembles mapped onto the 1UBQ X-ray structure. (C) Theoretical B-factors from a Gaussian Network Model. Color coding for B, C and D: Green: 0–25% of the max value in the non-loop regions; Yellow: 25–50% of the max; Orange: 50–75% of the max; Red: 75–100% of the max; Grey: loop regions that were not included in the fit to the RDC measurements.
Mentions: The structural variability of the ensemble is illustrated in Figure 4A. The average NH order parameter in regular secondary structure elements is 0.76, the same as that computed for the model free analysis (0.77) described in Lakomek et al., but lower than that computed for the EROS ensemble (0.83) [4],[35].

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