Dataset Information

Large-scale motions in the adenylate kinase solution ensemble: coarse-grained simulations and comparison with solution X-ray scattering.

ABSTRACT: While coarse-grained (CG) simulations provide an efficient approach to identify small- and large-scale motions important to protein conformational transitions, coupling with appropriate experimental validation is essential. Here, by comparing small-angle X-ray scattering (SAXS) predictions from CG simulation ensembles of adenylate kinase (AK) with a range of energetic parameters, we demonstrate that AK is flexible in solution in the absence of ligand and that a small population of the closed form exists without ligand. In addition, by analyzing variation of scattering patterns within CG simulation ensembles, we reveal that rigid-body motion of the LID domain corresponds to a dominant scattering feature. Thus, we have developed a novel approach for three-dimensional structural interpretation of SAXS data. Finally, we demonstrate that the agreement between predicted and experimental SAXS can be improved by increasing the simulation temperature or by computationally mutating selected residues to glycine, both of which perturb LID rigid-body flexibility.

SUBMITTER: Daily MD

PROVIDER: S-EPMC3375699 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Large-scale motions in the adenylate kinase solution ensemble: coarse-grained simulations and comparison with solution X-ray scattering.

Daily Michael D MD Makowski Lee L Phillips George N GN Cui Qiang Q

Chemical physics 20120301

While coarse-grained (CG) simulations provide an efficient approach to identify small- and large-scale motions important to protein conformational transitions, coupling with appropriate experimental validation is essential. Here, by comparing small-angle X-ray scattering (SAXS) predictions from CG simulation ensembles of adenylate kinase (AK) with a range of energetic parameters, we demonstrate that AK is flexible in solution in the absence of ligand and that a small population of the closed for ...[more]

PMID: 22711968

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Project description:BackgroundGenome sequencing projects have expanded the gap between the amount of known protein sequences and structures. The limitations of current high resolution structure determination methods make it unlikely that this gap will disappear in the near future. Small angle X-ray scattering (SAXS) is an established low resolution method for routinely determining the structure of proteins in solution. The purpose of this study is to develop a method for the efficient calculation of accurate SAXS curves from coarse-grained protein models. Such a method can for example be used to construct a likelihood function, which is paramount for structure determination based on statistical inference.ResultsWe present a method for the efficient calculation of accurate SAXS curves based on the Debye formula and a set of scattering form factors for dummy atom representations of amino acids. Such a method avoids the computationally costly iteration over all atoms. We estimated the form factors using generated data from a set of high quality protein structures. No ad hoc scaling or correction factors are applied in the calculation of the curves. Two coarse-grained representations of protein structure were investigated; two scattering bodies per amino acid led to significantly better results than a single scattering body.ConclusionWe show that the obtained point estimates allow the calculation of accurate SAXS curves from coarse-grained protein models. The resulting curves are on par with the current state-of-the-art program CRYSOL, which requires full atomic detail. Our method was also comparable to CRYSOL in recognizing native structures among native-like decoys. As a proof-of-concept, we combined the coarse-grained Debye calculation with a previously described probabilistic model of protein structure, TorusDBN. This resulted in a significant improvement in the decoy recognition performance. In conclusion, the presented method shows great promise for use in statistical inference of protein structures from SAXS data.

Dataset Information

Large-scale motions in the adenylate kinase solution ensemble: coarse-grained simulations and comparison with solution X-ray scattering.

Publications

Large-scale motions in the adenylate kinase solution ensemble: coarse-grained simulations and comparison with solution X-ray scattering.

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