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Using molecular principal axes for structural comparison: determining the tertiary changes of a FAB antibody domain induced by antigenic binding.

Silverman BD - BMC Struct. Biol. (2007)

Bottom Line: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

View Article: PubMed Central - HTML - PubMed

Affiliation: IBM Thomas J, Watson Research Center P, O, Box 218, Yorktown Heights, NY 10598, USA. silverma@us.ibm.com

ABSTRACT

Background: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.

Results: A new approach is applied to determine the structural changes that an antibody protein domain experiences upon its interaction with an antigenic target. These changes are determined with the use of two different, however comparable, sets of principal axes that are obtained by diagonalizing the second-order tensors that yield the moments-of-geometry as well as an ellipsoidal characterization of domain shape, prior to and after interaction. Determination of these sets of axes for structural comparison requires no internal symmetry features of the domains, depending solely upon their representation in three-dimensional space. This representation may involve atomic, Calpha, or residue centroid coordinates. The present analysis utilizes residue centroids. When the structural changes are minimal, the principal axes of the domains, prior to and after interaction, are essentially comparable and consequently may be used for structural comparison. When the differences of the axes cannot be neglected, but are nevertheless slight, a smaller relatively invariant substructure of the domains may be utilized for comparison. The procedure yields two distance metrics for structural comparison. First, the displacements of the residue centroids due to antigenic binding, referenced to the ellipsoidal principal axes, are noted. Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.

Conclusion: With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

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The spatial disposition of amino acids, ASP99, GLU100, and ASN100A of the H3 loop of the heavy chain, A. before (PDB 1HIL) and B. after (PDB 1IFH) complexing with the antigenic mimetic.
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Figure 11: The spatial disposition of amino acids, ASP99, GLU100, and ASN100A of the H3 loop of the heavy chain, A. before (PDB 1HIL) and B. after (PDB 1IFH) complexing with the antigenic mimetic.

Mentions: Complementary information is again provided by a comparison of the displacements shown in figure 9B with the changes in ellipsoidal distances upon complexing indicated by figure 9D. This comparison shows that while a number of residues of the H3 loop are significantly displaced, some move towards the domain interior of the heavy chain while others move away. Figure 11 is ball and stick representation of three of the residues that are significantly displaced upon complexing. Due to the severe H3 loop distortion upon binding this triplet is rotated from an orientation in which a residue initially pointing either up or down in figure 11A prior to complexing is reversed in direction in figure 11B after complexing. Note, that aside from the H3 loop distortion, the heavy chain orientation has been held relatively fixed in both of the figures. All three of these residues have, therefore, experienced a significant displacement, as shown in figure 11B, from their location prior to complexing. However, while, GLU100 moves away from the center of the N-terminal domain of the heavy chain upon binding, a rotation about its CA-CB bond enhances the motion of the residue centroids, ASP99 and ASN100A, to locations that are respectively, nearer to or more distant from the center of the heavy domain. All of these movements of these three amino acids are summarized simply by the complementary information provided by the two figures, 9B and 9D.


Using molecular principal axes for structural comparison: determining the tertiary changes of a FAB antibody domain induced by antigenic binding.

Silverman BD - BMC Struct. Biol. (2007)

The spatial disposition of amino acids, ASP99, GLU100, and ASN100A of the H3 loop of the heavy chain, A. before (PDB 1HIL) and B. after (PDB 1IFH) complexing with the antigenic mimetic.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2238760&req=5

Figure 11: The spatial disposition of amino acids, ASP99, GLU100, and ASN100A of the H3 loop of the heavy chain, A. before (PDB 1HIL) and B. after (PDB 1IFH) complexing with the antigenic mimetic.
Mentions: Complementary information is again provided by a comparison of the displacements shown in figure 9B with the changes in ellipsoidal distances upon complexing indicated by figure 9D. This comparison shows that while a number of residues of the H3 loop are significantly displaced, some move towards the domain interior of the heavy chain while others move away. Figure 11 is ball and stick representation of three of the residues that are significantly displaced upon complexing. Due to the severe H3 loop distortion upon binding this triplet is rotated from an orientation in which a residue initially pointing either up or down in figure 11A prior to complexing is reversed in direction in figure 11B after complexing. Note, that aside from the H3 loop distortion, the heavy chain orientation has been held relatively fixed in both of the figures. All three of these residues have, therefore, experienced a significant displacement, as shown in figure 11B, from their location prior to complexing. However, while, GLU100 moves away from the center of the N-terminal domain of the heavy chain upon binding, a rotation about its CA-CB bond enhances the motion of the residue centroids, ASP99 and ASN100A, to locations that are respectively, nearer to or more distant from the center of the heavy domain. All of these movements of these three amino acids are summarized simply by the complementary information provided by the two figures, 9B and 9D.

Bottom Line: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

View Article: PubMed Central - HTML - PubMed

Affiliation: IBM Thomas J, Watson Research Center P, O, Box 218, Yorktown Heights, NY 10598, USA. silverma@us.ibm.com

ABSTRACT

Background: Comparison of different protein x-ray structures has previously been made in a number of different ways; for example, by visual examination, by differences in the locations of secondary structures, by explicit superposition of structural elements, e.g. alpha-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.

Results: A new approach is applied to determine the structural changes that an antibody protein domain experiences upon its interaction with an antigenic target. These changes are determined with the use of two different, however comparable, sets of principal axes that are obtained by diagonalizing the second-order tensors that yield the moments-of-geometry as well as an ellipsoidal characterization of domain shape, prior to and after interaction. Determination of these sets of axes for structural comparison requires no internal symmetry features of the domains, depending solely upon their representation in three-dimensional space. This representation may involve atomic, Calpha, or residue centroid coordinates. The present analysis utilizes residue centroids. When the structural changes are minimal, the principal axes of the domains, prior to and after interaction, are essentially comparable and consequently may be used for structural comparison. When the differences of the axes cannot be neglected, but are nevertheless slight, a smaller relatively invariant substructure of the domains may be utilized for comparison. The procedure yields two distance metrics for structural comparison. First, the displacements of the residue centroids due to antigenic binding, referenced to the ellipsoidal principal axes, are noted. Second, changes in the ellipsoidal distances with respect to the non-interacting structure provide a direct measure of the spatial displacements of the residue centroids, towards either the interior or exterior of the domain.

Conclusion: With use of x-ray data from the protein data bank (PDB), these two metrics are shown to highlight, in a manner different from before, the structural changes that are induced in the overall domains as well as in the H3 loops of the complementarity-determining regions (CDR) upon FAB antibody binding to a truncated and to a synthetic hemagglutinin viral antigenic target.

Show MeSH