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Publication Detail
Motional timescale predictions by molecular dynamics simulations: Case study using proline and hydroxyproline sidechain dynamics.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Aliev AE, Kulke M, Khaneja HS, Chudasama V, Sheppard TD, Lanigan RM
  • Publication date:
  • Journal:
  • Language:
  • Keywords:
    NMR, biomolecular force field, conformational analysis, molecular dynamics simulations, peptides, proline, proteins, structure
  • Addresses:
    Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, U.K.
We propose a new approach for force field optimisations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use (13) C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field parameters against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimisation. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone. © Proteins 2013;. © 2013 Wiley Periodicals, Inc.
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