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Development and Validation of the QUBE Protein Force Field

preprint
revised on 23.07.2019, 10:44 and posted on 23.07.2019, 17:08 by Alice Allen, Michael J. Robertson, Michael C. Payne, Daniel Cole

Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus they neglect system-specific polarization. In this paper, we introduce a complete protein force field that is designed to be compatible with the QUantum mechanical BEspoke (QUBE) force field by deriving non-bonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are re-derived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE non-bonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, are tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely-used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. With several avenues for further development, the use of system-specific non-bonded force field parameters is a promising approach for next-generation simulations of biological molecules.

Funding

EPSRC EP/R010153/1, EP/L015552/1, EP/J017639/1 and EP/P020259/1

History

Email Address of Submitting Author

daniel.cole@ncl.ac.uk

Institution

Newcastle University

Country

United Kingdom

ORCID For Submitting Author

0000-0003-2933-0719

Declaration of Conflict of Interest

No conflict of interest

Licence

Exports