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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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Example of structural alignment for a superfamily. All the domains are pairwise aligned against the reference domain. Purple discontinuous box: Domain excluded of the analysis because -ln(E) < 5. Red box: core of the alignment, composed by all the aminoacids of the reference domain aligned at least once and their correspondences. Blue box: Example of reference residue aligned with gaps (core quality: 1/6 = 17%). Green box: reference residue aligned without gaps (core quality: 6/6 = 100%). Black box: Reference residue that is not part of the core because there is not variation info for it (never aligned. Core quality 0/6 = 0%).
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Figure 9: Example of structural alignment for a superfamily. All the domains are pairwise aligned against the reference domain. Purple discontinuous box: Domain excluded of the analysis because -ln(E) < 5. Red box: core of the alignment, composed by all the aminoacids of the reference domain aligned at least once and their correspondences. Blue box: Example of reference residue aligned with gaps (core quality: 1/6 = 17%). Green box: reference residue aligned without gaps (core quality: 6/6 = 100%). Black box: Reference residue that is not part of the core because there is not variation info for it (never aligned. Core quality 0/6 = 0%).

Mentions: In order to get results from a varied and representative number of superfamilies, we looked for structural diversity, non-redundancy, and good distribution of domain size. Additionally, enough number of structures and a good percentage of the reference domain sequence length forming the core of the alignment was another selection criterion. In total, we finally selected 55 superfamilies in CATH version v3.0.0 containing at least 20 non-redundant members (redundancy defined as 95% of sequence identity or higher), belonging to all possible structural classes (α, β, α+β), and with a good span in sequence size (30–459 aa). The decomposition of the conformational space defined by a given superfamily was done following the same approach developed for flexible fitting in tridimensional electron microscopy (3D-EM) in the presence of incomplete data [21]. All the domains of the superfamily were structurally aligned using MAMMOTH [28] against the reference domain, that was studied with MD (Figure 1). The domains with a statistical significance score of -ln(E) > 5 as provided by MAMMOTH where used to build the core of the structural alignment for the superfamily (red box, Figure 9), being the rest excluded (purple discontinuous domain, Figure 9). The condition for an aminoacid of the reference domain to be part of the core is to be aligned at least once with the rest of the superfamily members (example in blue box, Figure 9). The 55 superfamilies selected for this study had at least 10 domains and 68% of the reference domain sequence length belonging to the core, with most of them showing even a higher value (90%), thus providing data with as least missing values as possible.


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)

Example of structural alignment for a superfamily. All the domains are pairwise aligned against the reference domain. Purple discontinuous box: Domain excluded of the analysis because -ln(E) < 5. Red box: core of the alignment, composed by all the aminoacids of the reference domain aligned at least once and their correspondences. Blue box: Example of reference residue aligned with gaps (core quality: 1/6 = 17%). Green box: reference residue aligned without gaps (core quality: 6/6 = 100%). Black box: Reference residue that is not part of the core because there is not variation info for it (never aligned. Core quality 0/6 = 0%).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Example of structural alignment for a superfamily. All the domains are pairwise aligned against the reference domain. Purple discontinuous box: Domain excluded of the analysis because -ln(E) < 5. Red box: core of the alignment, composed by all the aminoacids of the reference domain aligned at least once and their correspondences. Blue box: Example of reference residue aligned with gaps (core quality: 1/6 = 17%). Green box: reference residue aligned without gaps (core quality: 6/6 = 100%). Black box: Reference residue that is not part of the core because there is not variation info for it (never aligned. Core quality 0/6 = 0%).
Mentions: In order to get results from a varied and representative number of superfamilies, we looked for structural diversity, non-redundancy, and good distribution of domain size. Additionally, enough number of structures and a good percentage of the reference domain sequence length forming the core of the alignment was another selection criterion. In total, we finally selected 55 superfamilies in CATH version v3.0.0 containing at least 20 non-redundant members (redundancy defined as 95% of sequence identity or higher), belonging to all possible structural classes (α, β, α+β), and with a good span in sequence size (30–459 aa). The decomposition of the conformational space defined by a given superfamily was done following the same approach developed for flexible fitting in tridimensional electron microscopy (3D-EM) in the presence of incomplete data [21]. All the domains of the superfamily were structurally aligned using MAMMOTH [28] against the reference domain, that was studied with MD (Figure 1). The domains with a statistical significance score of -ln(E) > 5 as provided by MAMMOTH where used to build the core of the structural alignment for the superfamily (red box, Figure 9), being the rest excluded (purple discontinuous domain, Figure 9). The condition for an aminoacid of the reference domain to be part of the core is to be aligned at least once with the rest of the superfamily members (example in blue box, Figure 9). The 55 superfamilies selected for this study had at least 10 domains and 68% of the reference domain sequence length belonging to the core, with most of them showing even a higher value (90%), thus providing data with as least missing values as possible.

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