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Protein flexibility: coordinate uncertainties and interpretation of structural differences.

ABSTRACT: Valid interpretations of conformational movements in protein structures determined by X-ray crystallography require that the movement magnitudes exceed their uncertainty threshold. Here, it is shown that such thresholds can be obtained from the distance difference matrices (DDMs) of 1014 pairs of independently determined structures of bovine ribonuclease A and sperm whale myoglobin, with no explanations provided for reportedly minor coordinate differences. The smallest magnitudes of reportedly functional motions are just above these thresholds. Uncertainty thresholds can provide objective criteria that distinguish between true conformational changes and apparent 'noise', showing that some previous interpretations of protein coordinate changes attributed to external conditions or mutations may be doubtful or erroneous. The use of uncertainty thresholds, DDMs, the newly introduced CDDMs (contact distance difference matrices) and a novel simple rotation algorithm allows a more meaningful classification and description of protein motions, distinguishing between various rigid-fragment motions and nonrigid conformational deformations. It is also shown that half of 75 pairs of identical molecules, each from the same asymmetric crystallographic cell, exhibit coordinate differences that range from just outside the coordinate uncertainty threshold to the full magnitude of large functional movements. Thus, crystallization might often induce protein conformational changes that are comparable to those related to or induced by the protein function.

SUBMITTER: Rashin AA

PROVIDER: S-EPMC2777169 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Protein flexibility: coordinate uncertainties and interpretation of structural differences.

Rashin Alexander A AA Rashin Abraham H L AH Jernigan Robert L RL

Acta crystallographica. Section D, Biological crystallography 20091022 Pt 11

Valid interpretations of conformational movements in protein structures determined by X-ray crystallography require that the movement magnitudes exceed their uncertainty threshold. Here, it is shown that such thresholds can be obtained from the distance difference matrices (DDMs) of 1014 pairs of independently determined structures of bovine ribonuclease A and sperm whale myoglobin, with no explanations provided for reportedly minor coordinate differences. The smallest magnitudes of reportedly f ...[more]

PMID: 19923711

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Project description:Currently a huge amount of protein-protein interaction data is available from high throughput experimental methods. In a large network of protein-protein interactions, groups of proteins can be identified as functional clusters having related functions where a single protein can occur in multiple clusters. However experimental methods are error-prone and thus the interactions in a functional cluster may include false positives or there may be unreported interactions. Therefore correctly identifying a functional cluster of proteins requires the knowledge of whether any two proteins in a cluster interact, whether an interaction can exclude other interactions, or how strong the affinity between two interacting proteins is.In the present work the yeast protein-protein interaction network is clustered using a spectral clustering method proposed by us in 2006 and the individual clusters are investigated for functional relationships among the member proteins. 3D structural models of the proteins in one cluster have been built--the protein structures are retrieved from the Protein Data Bank or predicted using a comparative modeling approach. A rigid body protein docking method (Cluspro) is used to predict the protein-protein interaction complexes. Binding sites of the docked complexes are characterized by their buried surface areas in the docked complexes, as a measure of the strength of an interaction.The clustering method yields functionally coherent clusters. Some of the interactions in a cluster exclude other interactions because of shared binding sites. New interactions among the interacting proteins are uncovered, and thus higher order protein complexes in the cluster are proposed. Also the relative stability of each of the protein complexes in the cluster is reported.Although the methods used are computationally expensive and require human intervention and judgment, they can identify the interactions that could occur together or ones that are mutually exclusive. In addition indirect interactions through another intermediate protein can be identified. These theoretical predictions might be useful for crystallographers to select targets for the X-ray crystallographic determination of protein complexes.

Project description:BackgroundInterpretation of shoulder motion across studies has been complicated due to the use of numerous scapular coordinate systems in the literature. Currently, there are no simple means by which to compare scapular kinematics between coordinate system definitions when data from only one coordinate system is known.Research questionHow do scapular kinematics vary based on the choice of coordinate system and can average rotation matrices be used to accurately convert kinematics between scapular local coordinate systems?MethodsAverage rotation matrices derived from anatomic landmarks of 51 cadaver scapulae (29 M/22 F; 59 ± 13 yrs; 26R/25 L; 171 ± 11 cm; 70 ± 19 kg; 23.7 ± 5.5 kg/m2) were generated between three common scapular coordinate systems. Absolute angle of rotation was used to determine if anatomical variability within the cadaver population influenced the matrices. To quantify the predictive capability to convert kinematics between the three coordinate systems, the average rotation matrices were applied to scapulothoracic motion data collected from 19 human subjects (10 M/9 F; 43 ± 17 yrs; 19R; 173 ± 9 cm; 71 ± 16 kg; 23.6 ± 4.5 kg/m2) using biplane fluoroscopy. Root mean squared error (RMSE) was used to compare kinematics from an original coordinate system to the kinematics expressed in each alternative coordinate system.ResultsThe choice of scapular coordinate system resulted in mean differences in scapulothoracic rotation of up to 23°, with overall different shapes and/or magnitudes of the curves. A single average rotation matrix between any two coordinate systems achieved accurate conversion of scapulothoracic kinematics to within 4° of RMSE of the known solution. The average rotation matrices were independent of sex, side, decomposition sequence, and motion.SignificanceScapulothoracic kinematic representations vary in shape and magnitude based solely on the choice of local coordinate system. The results of this study enhance interpretability and reproducibility in expressing scapulothoracic motion data between laboratories by providing a simple means to convert data between common coordinate systems. This is necessitated by the variety of available motion analysis techniques and their respective scapular landmark definitions.

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Protein flexibility: coordinate uncertainties and interpretation of structural differences.

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Protein flexibility: coordinate uncertainties and interpretation of structural differences.

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