Dataset Information

Obtaining Tertiary Protein Structures by the ab Initio Interpretation of Small Angle X-ray Scattering Data.

ABSTRACT: Small angle X-ray scattering (SAXS) is an important tool for investigating the structure of proteins in solution. We present a novel ab initio method representing polypeptide chains as discrete curves used to derive a meaningful three-dimensional model from only the primary sequence and SAXS data. High resolution structures were used to generate probability density functions for each common secondary structural element found in proteins, which are used to place realistic restraints on the model curve's geometry. This is coupled with a novel explicit hydration shell model in order to derive physically meaningful three-dimensional models by optimizing against experimental SAXS data. The efficacy of this model is verified on an established benchmark protein set, and then it is used to predict the lysozyme structure using only its primary sequence and SAXS data. The method is used to generate a biologically plausible model of the coiled-coil component of the human synaptonemal complex central element protein.

SUBMITTER: Prior C

PROVIDER: S-EPMC7145352 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Obtaining Tertiary Protein Structures by the ab Initio Interpretation of Small Angle X-ray Scattering Data.

Prior Christopher C Davies Owen R OR Bruce Daniel D Pohl Ehmke E

Journal of chemical theory and computation 20200218 3

Small angle X-ray scattering (SAXS) is an important tool for investigating the structure of proteins in solution. We present a novel ab initio method representing polypeptide chains as discrete curves used to derive a meaningful three-dimensional model from <i>only</i> the primary sequence and SAXS data. High resolution structures were used to generate probability density functions for each common secondary structural element found in proteins, which are used to place realistic restraints on the ...[more]

PMID: 32023061

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Project description:Complementary strategies of small-angle x-ray scattering (SAXS) and crystallographic analysis are often used to determine atomistic three-dimensional models of macromolecules and their variability in solution. This combination of techniques is particularly valuable when applied to macromolecular complexes to detect changes within the individual binding partners. Here, we determine the x-ray crystallographic structure of a F(ab) fragment in complex with CD32b, the only inhibitory Fc-γ receptor in humans, and compare the structure of the F(ab) from the crystal complex to SAXS data for the F(ab) alone in solution. We investigate changes in F(ab) structure by predicting theoretical scattering profiles for atomistic structures extracted from molecular dynamics (MD) simulations of the F(ab) and assessing the agreement of these structures to our experimental SAXS data. Through principal component analysis, we are able to extract principal motions observed during the MD trajectory and evaluate the influence of these motions on the agreement of structures to the F(ab) SAXS data. Changes in the F(ab) elbow angle were found to be important to reach agreement with the experimental data; however, further discrepancies were apparent between our F(ab) structure from the crystal complex and SAXS data. By analyzing multiple MD structures observed in similar regions of the principal component analysis, we were able to pinpoint these discrepancies to a specific loop region in the F(ab) heavy chain. This method, therefore, not only allows determination of global changes but also allows identification of localized motions important for determining the agreement between atomistic structures and SAXS data. In this particular case, the findings allowed us to discount the hypothesis that structural changes were induced upon complex formation, a significant find informing the drug development process. The methodology described here is generally applicable to deconvolute global and local changes of macromolecular structures and is well suited to other systems.

Dataset Information

Obtaining Tertiary Protein Structures by the ab Initio Interpretation of Small Angle X-ray Scattering Data.

Publications

Obtaining Tertiary Protein Structures by the ab Initio Interpretation of Small Angle X-ray Scattering Data.

Similar Datasets

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