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  Structural ensembles of intrinsically disordered proteins depend strongly on force field: A comparison to experiment.

Rauscher, S., Gapsys, V., Gajda, M. J., Zweckstetter, M., de Groot, B. L., & Grubmüller, H. (2015). Structural ensembles of intrinsically disordered proteins depend strongly on force field: A comparison to experiment. Journal of Chemical Theory and Computation, 11(11), 5513-5524. doi:10.1021/acs.jctc.5b00736.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-1E74-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-2861-1
Genre: Journal Article

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 Creators:
Rauscher, S.1, Author              
Gapsys, V.2, Author              
Gajda, M. J.3, Author              
Zweckstetter, M.3, Author              
de Groot, B. L.2, Author              
Grubmüller, H.1, Author              
Affiliations:
1Department of Theoretical and Computational Biophysics, MPI for Biophysical Chemistry, Max Planck Society, ou_578631              
2Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              
3Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              

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 Abstract: Intrinsically disordered proteins (IDPs) are notoriously challenging to study both experimentally and computationally. The structure of IDPs cannot be described by a single conformation but must instead be described as an ensemble of interconverting conformations. Atomistic simulations are increasingly used to obtain such IDP conformational ensembles. Here, we have compared the IDP ensembles generated by eight all-atom empirical force fields against primary small-angle X-ray scattering (SAXS) and NMR data. Ensembles obtained with different force fields exhibit marked differences in chain dimensions, hydrogen bonding, and secondary structure content. These differences are unexpectedly large: changing the force field is found to have a stronger effect on secondary structure content than changing the entire peptide sequence. The CHARMM 22* ensemble performs best in this force field comparison: it has the lowest error in chemical shifts and J-couplings and agrees well with the SAXS data. A high population of left-handed α-helix is present in the CHARMM 36 ensemble, which is inconsistent with measured scalar couplings. To eliminate inadequate sampling as a reason for differences between force fields, extensive simulations were carried out (0.964 ms in total); the remaining small sampling uncertainty is shown to be much smaller than the observed differences. Our findings highlight how IDPs, with their rugged energy landscapes, are highly sensitive test systems that are capable of revealing force field deficiencies and, therefore, contributing to force field development.

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Language(s): eng - English
 Dates: 2015-10-092015-11-10
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jctc.5b00736
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Title: Journal of Chemical Theory and Computation
Source Genre: Journal
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Pages: - Volume / Issue: 11 (11) Sequence Number: - Start / End Page: 5513 - 5524 Identifier: -