Car-Parrinello molecular dynamics simulations were performed for N-methyl acetamide as a small test system for amide groups in protein backbones, and NMR chemical shifts were calculated based on the generated ensemble. If conformational sampling and explicit solvent molecules are taken into account, excellent agreement between the calculated and experimental chemical shifts is obtained. These results represent a landmark improvement over calculations based on classical molecular dynamics (MD) simulations especially for amide protons, which are predicted too high-field shifted based on the latter ensembles. We were able to show that the better results are caused by the solute-solvents interactions forming shorter hydrogen bonds as well as by the internal degrees of freedom of the solute. Inspired by these results, we propose our approach as a new tool for the validation of force fields due to its power of identifying the structural reasons for discrepancies between the experimental and calculated data.

Department of Chemistry Durham University DH1 3LE Durham United Kingdom

Department of Chemistry University of Konstanz 78457 Konstanz Germany

Institute of Organic Chemistry and Biochemistry Academy of Sciences Flemingovo náměstí 2 166 10 Prague Czech Republic

Theoretical Medicinal Chemistry and Biophysics Institute of Pharmacy Eberhard Karls University Tübingen Auf der Morgenstelle 8 72076 Tübingen Germany

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