Abstract
BackgroundComparison 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. α-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared.ResultsA 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, Cα, 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.ConclusionWith 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.
Highlights
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. α-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared
A singular advantage of such procedure, compared with the other procedures, is that it provides additional information that relates the location of the residues to attributes of the geometrical feature to which these locations have been aligned or referenced
The representation of such shape may be given by the distribution of atomic, Cα, or residue centroid locations in three-dimensional space. Such representation, generating an ellipsoidal characterization of the shape of a domain, had previously provided useful information in connection with drug discovery [3] and with the spatial distribution of residue hydrophobicity within protein domains [4]. This characterization of domain shape provides two spatial metrics, one of which references the location of a residue to the ellipsoidal principal axes of the domain and the other which yields information detailing the proximity of a residue to either the interior or exterior of the protein domain
Summary
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. α-carbon atom locations, or by procedures that utilize a common symmetry element or geometrical feature of the structures to be compared This latter procedure has been utilized in connection with the identification of the structurally conserved residues within the core of the immunoglobulin variable domains [1]. The overall shape or distribution of the amino acid residues of a protein domain may be considered a geometric invariant of a set of structures undergoing comparison when the differences in their global geometries are small and involve only a minor fraction of the residues comprising the domains The representation of such shape may be given by the distribution of atomic, Cα, or residue centroid locations in three-dimensional space. The present paper describes how the changes in antibody structure that occur upon binding to an antigenic target are characterized by the consequent changes of these two metrics
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