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  Probing the accuracy of explicit solvent constant pH molecular dynamics simulations for peptides

Dobrev, P., Vemulapalli, S. P., Nath, N., Griesinger, C., & Grubmüller, H. (2020). Probing the accuracy of explicit solvent constant pH molecular dynamics simulations for peptides. Journal of Chemical Theory and Computation, 16(4), 2561-2569. doi:10.1021/acs.jctc.9b01232.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-DF2B-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-DF35-4
Genre: Journal Article

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 Creators:
Dobrev, P.1, Author              
Vemulapalli, S. P.2, Author              
Nath, N.2, Author              
Griesinger, C.3, Author              
Grubmüller, H.1, Author              
Affiliations:
1Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              
2Department of NMR Based Structural Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_578567              
3Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Peptides and proteins, Reaction mechanisms, Monomers, Potential energy, Titration
 Abstract: Protonation 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.

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Language(s): eng - English
 Dates: 2020-03-192020-04-14
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.jctc.9b01232
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Title: Journal of Chemical Theory and Computation
Source Genre: Journal
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Pages: - Volume / Issue: 16 (4) Sequence Number: - Start / End Page: 2561 - 2569 Identifier: -