Combining NMR ensembles and molecular dynamics simulations provides more realistic models of protein structures in solution and leads to better chemical shift prediction |
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Authors: | Juuso Lehtivarjo Kari Tuppurainen Tommi Hassinen Reino Laatikainen Mikael Peräkylä |
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Institution: | (1) School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland;(2) Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland |
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Abstract: | While chemical shifts are invaluable for obtaining structural information from proteins, they also offer one of the rare ways
to obtain information about protein dynamics. A necessary tool in transforming chemical shifts into structural and dynamic
information is chemical shift prediction. In our previous work we developed a method for 4D prediction of protein 1H chemical shifts in which molecular motions, the 4th dimension, were modeled using molecular dynamics (MD) simulations. Although
the approach clearly improved the prediction, the X-ray structures and single NMR conformers used in the model cannot be considered
fully realistic models of protein in solution. In this work, NMR ensembles (NMRE) were used to expand the conformational space
of proteins (e.g. side chains, flexible loops, termini), followed by MD simulations for each conformer to map the local fluctuations.
Compared with the non-dynamic model, the NMRE+MD model gave 6–17% lower root-mean-square (RMS) errors for different backbone
nuclei. The improved prediction indicates that NMR ensembles with MD simulations can be used to obtain a more realistic picture
of protein structures in solutions and moreover underlines the importance of short and long time-scale dynamics for the prediction.
The RMS errors of the NMRE+MD model were 0.24, 0.43, 0.98, 1.03, 1.16 and 2.39 ppm for 1Hα, 1HN, 13Cα, 13Cβ, 13CO and backbone 15N chemical shifts, respectively. The model is implemented in the prediction program 4DSPOT, available at . |
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