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Unraveling low-resolution structural data of large biomolecules by constructing atomic models with experiment-targeted parallel cascade selection simulations.

ABSTRACT: Various low-resolution experimental techniques have gained more and more popularity in obtaining structural information of large biomolecules. In order to interpret the low-resolution structural data properly, one may need to construct an atomic model of the biomolecule by fitting the data using computer simulations. Here we develop, to our knowledge, a new computational tool for such integrative modeling by taking the advantage of an efficient sampling technique called parallel cascade selection (PaCS) simulation. For given low-resolution structural data, this PaCS-Fit method converts it into a scoring function. After an initial simulation starting from a known structure of the biomolecule, the scoring function is used to pick conformations for next cycle of multiple independent simulations. By this iterative screening-after-sampling strategy, the biomolecule may be driven towards a conformation that fits well with the low-resolution data. Our method has been validated using three proteins with small-angle X-ray scattering data and two proteins with electron microscopy data. In all benchmark tests, high-quality atomic models, with generally 1-3?Å from the target structures, are obtained. Since our tool does not need to add any biasing potential in the simulations to deform the structure, any type of low-resolution data can be implemented conveniently.

SUBMITTER: Peng J

PROVIDER: S-EPMC4932515 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Unraveling low-resolution structural data of large biomolecules by constructing atomic models with experiment-targeted parallel cascade selection simulations.

Peng Junhui J Zhang Zhiyong Z

Scientific reports 20160705

Various low-resolution experimental techniques have gained more and more popularity in obtaining structural information of large biomolecules. In order to interpret the low-resolution structural data properly, one may need to construct an atomic model of the biomolecule by fitting the data using computer simulations. Here we develop, to our knowledge, a new computational tool for such integrative modeling by taking the advantage of an efficient sampling technique called parallel cascade selectio ...[more]

PMID: 27377017

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Project description:Targeted protein degradation (TPD) has emerged as a powerful approach for removing (rather than inhibiting) proteins implicated in diseases. A key step in TPD is the formation of an induced proximity complex where a degrader molecule recruits an E3 ligase to the protein of interest (POI), facilitating the transfer of ubiquitin to the POI and initiating the proteasomal degradation process. Here, we address three critical aspects of the TPD process using atomistic simulations: 1) formation of the ternary complex induced by a degrader molecule, 2) conformational heterogeneity of the ternary complex, and 3) degradation efficiency via the full Cullin Ring Ligase (CRL) macromolecular assembly. We combine experimental biophysical data---in this case hydrogen-deuterium exchange mass spectrometry (HDX-MS, which measures the solvent exposure of protein residues)---with molecular dynamics (MD) simulations aided by enhanced sampling techniques to accurately predict ternary complex structures at atomic resolution. We demonstrate improved efficiency, accuracy, and reliability in the ternary structure predictions of the bromodomain of the cancer target SMARCA2 with the E3 ligase VHL mediated by three different degrader molecules. The simulations accurately reproduce X-ray crystal structures -- including a new structure that we determined in this work (PDB ID: 7S4E) -- with root mean square deviations (RMSD) of 1.1 to 1.6 \r{A}. The simulations also reveal a structural ensemble of low-energy conformations of the ternary complex. Snapshots from these simulations are used as seeds for additional simulations, where we perform 7.1 milliseconds of aggregate simulation time using Folding@home. The detailed free energy surface captures the crystal structure conformation within a low-energy basin and is consistent with solution-phase experimental data (HDX-MS and SAXS). Finally, we graft a structural ensemble of the ternary complexes onto the full CRL and perform enhanced sampling simulations, which suggest that differences in degradation efficiency may be related to the proximity distribution of lysine residues on the POI relative to the E2-loaded ubiquitin. Several of the predicted ubiquitinated lysine residues have been validated through a ubiquitin mapping proteomics experiment. DOI 10.1038/s41467-022-33575-4

Dataset Information

Unraveling low-resolution structural data of large biomolecules by constructing atomic models with experiment-targeted parallel cascade selection simulations.

Publications

Unraveling low-resolution structural data of large biomolecules by constructing atomic models with experiment-targeted parallel cascade selection simulations.

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