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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 variance. a) Total variance for the performed decompositions: ISVD of the SF-space, SVD of the partial MD-space containing as many snapshots as members in the superfamily (average values for 100 windows), and SVD of the MD-space containing the entire MD trajectory. The domains in the x-axis are sorted by increasing number of aminoacids. b) Ratio of SF- and MD-space variances against the number residues in the reference domain. c) Ratio of SF- and MD-space variances against number of superfamily  members (log scale).
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Figure 2: Comparisons based on variance. a) Total variance for the performed decompositions: ISVD of the SF-space, SVD of the partial MD-space containing as many snapshots as members in the superfamily (average values for 100 windows), and SVD of the MD-space containing the entire MD trajectory. The domains in the x-axis are sorted by increasing number of aminoacids. b) Ratio of SF- and MD-space variances against the number residues in the reference domain. c) Ratio of SF- and MD-space variances against number of superfamily members (log scale).

Mentions: To study the relative size of the MD- and SF-spaces, we computed their variance after matrix decomposition (see Figure 1) by summing the squares of all the singular values (see Methods section for details). We clearly observe that, in general, the SF-space of deformation is larger, having a variance between 2 and 25 times (in average 10 times, see Figure 2a) bigger than the MD-space. These results do not seem to be influenced by the fact that the MD-space is defined using many more structures than the SF-space, since the basic trend is kept when we restrict the calculations to a partial MD-space (named MDp) with just as many snapshots as experimental structures in the superfamily. There are only 3 cases among the 55 superfamilies analyzed in which this pattern is, without any clear reason, different (1piqA00, 1bo0000 and 1a17000). We have not found any apparent correlation between these three cases, neither structurally (they are mostly α, β and α, respectively) nor functionally (binding, enzyme, signaling). Interestingly, we do not find any relationship between the variance of the MD-space and the number of aminoacids of the domain, which can be explained considering that the factors producing more structural variability, such as flexible loops, are not affected by the size of a domain. On the contrary, the variance of the SF-space increases with the number of aminoacids of the protein (Figure 2a), which is reasonable given the linear relationship between protein length and possibilities of variation in composition through mutation. As a consequence of this different behavior of variance versus size, a rough increase in the ratio between SF- and MD-space variances with protein size is found (Figure 2b), and the same incremental tendency is observed for the variance ratio plotted against the number of superfamily members (Figure 2c). Again, a similar reasoning explains it: a greater size of the superfamily implies a parallel increase in the possibilities of sequence variation, while it does not affect the variance of 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 variance. a) Total variance for the performed decompositions: ISVD of the SF-space, SVD of the partial MD-space containing as many snapshots as members in the superfamily (average values for 100 windows), and SVD of the MD-space containing the entire MD trajectory. The domains in the x-axis are sorted by increasing number of aminoacids. b) Ratio of SF- and MD-space variances against the number residues in the reference domain. c) Ratio of SF- and MD-space variances against number of superfamily  members (log scale).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Comparisons based on variance. a) Total variance for the performed decompositions: ISVD of the SF-space, SVD of the partial MD-space containing as many snapshots as members in the superfamily (average values for 100 windows), and SVD of the MD-space containing the entire MD trajectory. The domains in the x-axis are sorted by increasing number of aminoacids. b) Ratio of SF- and MD-space variances against the number residues in the reference domain. c) Ratio of SF- and MD-space variances against number of superfamily members (log scale).
Mentions: To study the relative size of the MD- and SF-spaces, we computed their variance after matrix decomposition (see Figure 1) by summing the squares of all the singular values (see Methods section for details). We clearly observe that, in general, the SF-space of deformation is larger, having a variance between 2 and 25 times (in average 10 times, see Figure 2a) bigger than the MD-space. These results do not seem to be influenced by the fact that the MD-space is defined using many more structures than the SF-space, since the basic trend is kept when we restrict the calculations to a partial MD-space (named MDp) with just as many snapshots as experimental structures in the superfamily. There are only 3 cases among the 55 superfamilies analyzed in which this pattern is, without any clear reason, different (1piqA00, 1bo0000 and 1a17000). We have not found any apparent correlation between these three cases, neither structurally (they are mostly α, β and α, respectively) nor functionally (binding, enzyme, signaling). Interestingly, we do not find any relationship between the variance of the MD-space and the number of aminoacids of the domain, which can be explained considering that the factors producing more structural variability, such as flexible loops, are not affected by the size of a domain. On the contrary, the variance of the SF-space increases with the number of aminoacids of the protein (Figure 2a), which is reasonable given the linear relationship between protein length and possibilities of variation in composition through mutation. As a consequence of this different behavior of variance versus size, a rough increase in the ratio between SF- and MD-space variances with protein size is found (Figure 2b), and the same incremental tendency is observed for the variance ratio plotted against the number of superfamily members (Figure 2c). Again, a similar reasoning explains it: a greater size of the superfamily implies a parallel increase in the possibilities of sequence variation, while it does not affect the variance of 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