Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 3. Conformational Sampling and Explicit Solvents Model.

Fragment-based quantum chemical calculations are able to accurately calculate NMR chemical shifts even for very large molecules like proteins. But even with systematic optimization of the level of theory and basis sets as well as the use of implicit solvents models, some nuclei like polar protons and nitrogens suffer from poor predictions. Two properties of the real system, strongly influencing the experimental chemical shifts but almost always neglected in the calculations, will be discussed here in great detail: (1) conformational averaging and (2) interactions with first-shell solvent molecules. Classical molecular dynamics simulations in explicit water were carried out for obtaining a representative ensemble including the arrangement of neighboring solvent molecules, which was then subjected to quantum chemical calculations. We could demonstrate with the small test system N-methyl acetamide (NMA) that the calculated chemical shifts show immense variations of up to 6 ppm and 50 ppm for protons and nitrogens, respectively, depending on the snapshot taken from a classical molecular dynamics simulation. Applying the same approach to the HA2 domain of the influenza virus glycoprotein hemagglutinin, a 32-amino-acid-long polypeptide, and comparing averaged values to the experiment, chemical shifts of nonpolar protons and carbon atoms in proteins were calculated with unprecedented accuracy. Additionally, the mean absolute error could be reduced by a factor of 2.43 for polar protons, and reasonable correlations were obtained for nitrogen and carbonyl carbon in contrast to all other studies published so far.