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Comparison of molecular dynamics and superfamily spaces of protein domain deformation.

Velázquez-Muriel JA, Rueda M, Cuesta I, Pascual-Montano A, Orozco M, Carazo JM - BMC Struct. Biol. (2009)

Bottom Line: Theoretically, we obtained two conclusions.First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability.Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro Nacional de Biotecnología-CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain. javi.velazquez@gmail.com

ABSTRACT

Background: It is well known the strong relationship between protein structure and flexibility, on one hand, and biological protein function, on the other hand. Technically, protein flexibility exploration is an essential task in many applications, such as protein structure prediction and modeling. In this contribution we have compared two different approaches to explore the flexibility space of protein domains: i) molecular dynamics (MD-space), and ii) the study of the structural changes within superfamily (SF-space).

Results: Our analysis indicates that the MD-space and the SF-space display a significant overlap, but are still different enough to be considered as complementary. The SF-space space is wider but less complex than the MD-space, irrespective of the number of members in the superfamily. Also, the SF-space does not sample all possibilities offered by the MD-space, but often introduces very large changes along just a few deformation modes, whose number tend to a plateau as the number of related folds in the superfamily increases.

Conclusion: Theoretically, we obtained two conclusions. First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability. Second, that conformational changes from variation in a superfamily are larger and much simpler than those allowed by physical deformability. Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity. We expect this fact to have application in fields as 3D-EM/X-ray hybrid models or ab initio protein folding.

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Comparisons based on space similarity. a) Hess metric applied using as many singular vectors as members in the superfamily. The x-axis is sorted by increasing number of members in the superfamily (the name of the reference member is written). b) Z-score of the Hess metric for a random model (See Methods for details). c) Z-score* of the Hess metric for a pseudo-random model (See Methods for details).
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Figure 5: Comparisons based on space similarity. a) Hess metric applied using as many singular vectors as members in the superfamily. The x-axis is sorted by increasing number of members in the superfamily (the name of the reference member is written). b) Z-score of the Hess metric for a random model (See Methods for details). c) Z-score* of the Hess metric for a pseudo-random model (See Methods for details).

Mentions: To study the overlap between the SF- and MD-spaces, we computed the Hess metric employing as many vectors as members in the superfamily (see Methods). In the superfamilies studied in this work, the Hess metric ranges from 0.05 to 0.6, with mean equal to 0.3 (Figure 5a). The best overlaps are found for class α and β proteins, which are explained by their simple dynamics (α) or intrinsic rigidity (β) when compared to class α+β. We found that the Hess metric values are statistically significant and not due to simple chance (see Z-scores in Figure 5b) when the results are compared to a pure random background model. Large Z-scores were also obtained when the background protein model is obtained by forcing the random trajectory to maintain covalent connectivity (Figure 5c) and to avoid steric clashes. We interpret this low, but statistically significant overlap of the SF- and MD-spaces, as a proof that proteins sharing the same fold conserve at least some part of their physical deformability pattern in order to conserve function. The rest of the deformations happening inside a superfamily by modification of the composition occur orthogonally to the deformations in the MD-space.


Comparison of molecular dynamics and superfamily spaces of protein domain deformation.

Velázquez-Muriel JA, Rueda M, Cuesta I, Pascual-Montano A, Orozco M, Carazo JM - BMC Struct. Biol. (2009)

Comparisons based on space similarity. a) Hess metric applied using as many singular vectors as members in the superfamily. The x-axis is sorted by increasing number of members in the superfamily (the name of the reference member is written). b) Z-score of the Hess metric for a random model (See Methods for details). c) Z-score* of the Hess metric for a pseudo-random model (See Methods for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2666742&req=5

Figure 5: Comparisons based on space similarity. a) Hess metric applied using as many singular vectors as members in the superfamily. The x-axis is sorted by increasing number of members in the superfamily (the name of the reference member is written). b) Z-score of the Hess metric for a random model (See Methods for details). c) Z-score* of the Hess metric for a pseudo-random model (See Methods for details).
Mentions: To study the overlap between the SF- and MD-spaces, we computed the Hess metric employing as many vectors as members in the superfamily (see Methods). In the superfamilies studied in this work, the Hess metric ranges from 0.05 to 0.6, with mean equal to 0.3 (Figure 5a). The best overlaps are found for class α and β proteins, which are explained by their simple dynamics (α) or intrinsic rigidity (β) when compared to class α+β. We found that the Hess metric values are statistically significant and not due to simple chance (see Z-scores in Figure 5b) when the results are compared to a pure random background model. Large Z-scores were also obtained when the background protein model is obtained by forcing the random trajectory to maintain covalent connectivity (Figure 5c) and to avoid steric clashes. We interpret this low, but statistically significant overlap of the SF- and MD-spaces, as a proof that proteins sharing the same fold conserve at least some part of their physical deformability pattern in order to conserve function. The rest of the deformations happening inside a superfamily by modification of the composition occur orthogonally to the deformations in the MD-space.

Bottom Line: Theoretically, we obtained two conclusions.First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability.Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro Nacional de Biotecnología-CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain. javi.velazquez@gmail.com

ABSTRACT

Background: It is well known the strong relationship between protein structure and flexibility, on one hand, and biological protein function, on the other hand. Technically, protein flexibility exploration is an essential task in many applications, such as protein structure prediction and modeling. In this contribution we have compared two different approaches to explore the flexibility space of protein domains: i) molecular dynamics (MD-space), and ii) the study of the structural changes within superfamily (SF-space).

Results: Our analysis indicates that the MD-space and the SF-space display a significant overlap, but are still different enough to be considered as complementary. The SF-space space is wider but less complex than the MD-space, irrespective of the number of members in the superfamily. Also, the SF-space does not sample all possibilities offered by the MD-space, but often introduces very large changes along just a few deformation modes, whose number tend to a plateau as the number of related folds in the superfamily increases.

Conclusion: Theoretically, we obtained two conclusions. First, that function restricts the access to some flexibility patterns to evolution, as we observe that when a superfamily member changes to become another, the path does not completely overlap with the physical deformability. Second, that conformational changes from variation in a superfamily are larger and much simpler than those allowed by physical deformability. Methodologically, the conclusion is that both spaces studied are complementary, and have different size and complexity. We expect this fact to have application in fields as 3D-EM/X-ray hybrid models or ab initio protein folding.

Show MeSH
Related in: MedlinePlus