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  Accurately Predicting Protein pKa Values Using Nonequilibrium Alchemy

Wilson, C., Karttunen, M., de Groot, B. L., & Gapsys, V. (2023). Accurately Predicting Protein pKa Values Using Nonequilibrium Alchemy. Journal of Chemical Theory and Computation, 19(21), 7833-7845. doi:10.1021/acs.jctc.3c00721.

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Other : Accurately Predicting Protein pKa Values Using Nonequilibrium Alchemy
Other : Accurately Predicting Protein p<i>K</i> a Values Using Nonequilibrium Alchemy

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Wilson, C.J., Author
Karttunen, M., Author
de Groot, Berend L.1, 2, Author           
Gapsys, Vytautas1, 2, Author           
Affiliations:
1Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350132              
2Research Group of Computational Biomolecular Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, Göttingen, DE, ou_3350134              

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 Abstract: The stability, solubility, and function of a protein depend on both its net charge and the protonation states of its individual residues. pKa is a measure of the tendency for a given residue to (de)protonate at a specific pH. Although pKa values can be resolved experimentally, theory and computation provide a compelling alternative. To this end, we assess the applicability of a nonequilibrium (NEQ) alchemical free energy method to the problem of pKa prediction. On a data set of 144 residues that span 13 proteins, we report an average unsigned error of 0.77 ± 0.09, 0.69 ± 0.09, and 0.52 ± 0.04 pK for aspartate, glutamate, and lysine, respectively. This is comparable to current state-of-the-art predictors and the accuracy recently reached using free energy perturbation methods (e.g., FEP+). Moreover, we demonstrate that our open-source, pmx-based approach can accurately resolve the pKa values of coupled residues and observe a substantial performance disparity associated with the lysine partial charges in Amber14SB/Amber99SB*-ILDN, for which an underused fix already exists.

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Language(s): eng - English
 Dates: 2023-10-112023-11-14
 Publication Status: Issued
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 Rev. Type: Peer
 Identifiers: DOI: 10.1021/acs.jctc.3c00721
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Title: Journal of Chemical Theory and Computation
  Other : JCTC
  Abbreviation : J. Chem. Theory Comput.
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 19 (21) Sequence Number: - Start / End Page: 7833 - 7845 Identifier: ISSN: 1549-9618
CoNE: https://pure.mpg.de/cone/journals/resource/111088195283832