Dataset Information

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins.

ABSTRACT: Intrinsically disordered proteins (IDPs) or intrinsically disordered regions do not have a fixed tertiary structure but play key roles in signal regulation, molecule recognition, and drug targeting. However, it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored overcoming these limitations by developing the ff99IDPs and ff14IDPs force fields to correct the dihedral distribution for eight disorder-promoting residues often observed in IDPs and found encouraging improvements. Here we extend our correction of backbone dihedral terms to all 20 naturally occurring amino acids in the IDP-specific force field ff14IDPSFF to further improve the quality of the modeling of IDPs. Extensive tests of seven IDPs and 14 unstructured short peptides show that the simulated C? chemical shifts obtained with the ff14IDPSFF force field are in quantitative agreement with those from NMR experiments and are more accurate than those obtained with the base generic force field and also our previous ff14IDPs that only corrects the eight disorder-promoting amino acids. The influence of the solvent model was also investigated and found to be less important. Finally, our explicit-solvent MD simulations further show that ff14IDPSFF can still be used to model structural and dynamical properties of two tested folded proteins, with a slightly better agreement in the loop regions for both structural and dynamical properties. These findings confirm that the newly developed IDP-specific force field ff14IDPSFF can improve the conformer sampling of intrinsically disordered proteins.

SUBMITTER: Song D

PROVIDER: S-EPMC5731455 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins.

Song Dong D Luo Ray R Chen Hai-Feng HF

Journal of chemical information and modeling 20170504 5

Intrinsically disordered proteins (IDPs) or intrinsically disordered regions do not have a fixed tertiary structure but play key roles in signal regulation, molecule recognition, and drug targeting. However, it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored overcoming t ...[more]

PMID: 28448138

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Project description:Intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) play important roles in many aspects of normal cell physiology, such as signal transduction and transcription, as well as pathological states, including Alzheimer's, Parkinson's, and Huntington's disease. Unlike their globular counterparts that are defined by a few structures and free energy minima, IDP/IDR comprise a large ensemble of rapidly interconverting structures and a corresponding free energy landscape characterized by multiple minima. This aspect has precluded the use of structural biological techniques, such as X-ray crystallography and nuclear magnetic resonance (NMR) for resolving their structures. Instead, low-resolution techniques, such as small-angle X-ray or neutron scattering (SAXS/SANS), have become a mainstay in characterizing coarse features of the ensemble of structures. These are typically complemented with NMR data if possible or computational techniques, such as atomistic molecular dynamics, to further resolve the underlying ensemble of structures. However, over the past 10-15 years, it has become evident that the classical, pairwise-additive force fields that have enjoyed a high degree of success for globular proteins have been somewhat limited in modeling IDP/IDR structures that agree with experiment. There has thus been a significant effort to rehabilitate these models to obtain better agreement with experiment, typically done by optimizing parameters in a piecewise fashion. In this work, we take a different approach by optimizing a set of force field parameters simultaneously, using machine learning to adapt force field parameters to experimental SAXS scattering profiles. We demonstrate our approach in modeling three biologically IDP ensembles based on experimental SAXS profiles and show that our optimization approach significantly improve force field parameters that generate ensembles in better agreement with experiment.

Dataset Information

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins.

Publications

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins.

Similar Datasets

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