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Probing the Accuracy of Explicit Solvent Constant pH Molecular Dynamics Simulations for Peptides
journal contribution
posted on 2020-04-01, 11:42 authored by Plamen Dobrev, Sahithya Phani
Babu Vemulapalli, Nilamoni Nath, Christian Griesinger, Helmut GrubmüllerProtonation states of titratable
amino acids play a key role in many biomolecular processes. Knowledge
of protonatable residue charges at a given pH is essential for a correct
understanding of protein catalysis, inter- and intramolecular interactions,
substrate binding, and protein dynamics for instance. However, acquiring
experimental values for individual amino acid protonation states of
complex systems is not straightforward; therefore, several in silico approaches have been developed to tackle this
issue. In this work, we assess the accuracy of our previously developed
constant pH MD approach by comparing our theoretically obtained pKa values for titratable residues with experimental values from an
equivalent NMR study. We selected a set of four pentapeptides, of
adequately small size to ensure comprehensive sampling, but concurrently,
due to their charge composition, posing a challenge for protonation
state calculation. The comparison of the pKa values shows good agreement of the experimental
and the theoretical approach with a largest difference of 0.25 pKa units. Further, the corresponding
titration curves are in fair agreement, although the shift of the
Hill coefficient from a value of 1 was not always reproduced in simulations.
The phase space overlap in Cartesian space between trajectories generated
in constant pH and standard MD simulations is fair and suggests that
our constant pH MD approach reasonably well preserves the dynamics
of the system, allowing dynamic protonation MD simulations without
introducing structural artifacts.