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Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 3. Conformational Sampling and Explicit Solvents Model
journal contribution
posted on 2012-11-13, 00:00 authored by Thomas E. Exner, Andrea Frank, Ionut Onila, Heiko M. MöllerFragment-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.