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Title: On the development of protein pKa calculation algorithms

Abstract

Protein pKa calculation algorithms are typically developed to reproduce experimental pKa values and provide us with a better understanding of the fundamental importance of electrostatics for protein structure and function. However, the approximations and adjustable parameters employed in almost all pKa calculation methods means that there is the risk that pKa calculation algorithms are 'over-fitted' to the available datasets, and that these methods therefore do not model protein physics realistically. We employ simulations of the protein pKa calculation algorithm development process to show that careful optimization procedures and non-biased experimental datasets must be applied to ensure a realistic description of the underlying physical terms. We furthermore investigate the effect of experimental noise and find a significant effect on the pKa calculation algorithm optimization landscape. Finally, we comment on strategies for ensuring the physical realism of protein pKa calculation algorithms and we assess the overall state of the field with a view to predicting future directions of development.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1037531
Report Number(s):
PNNL-SA-77764
400412000; TRN: US201207%%337
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proteins. Structure, Function, and Bioinformatics; Journal Volume: 79; Journal Issue: 12
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ALGORITHMS; APPROXIMATIONS; CALCULATION METHODS; ELECTROSTATICS; OPTIMIZATION; PHYSICS; PROTEIN STRUCTURE; PROTEINS; pka; solvation; electrostatics

Citation Formats

Carstensen, Tommy, Farrell, Damien, Huang, Yong, Baker, Nathan A., and Nielsen, Jens E. On the development of protein pKa calculation algorithms. United States: N. p., 2011. Web. doi:10.1002/prot.23091.
Carstensen, Tommy, Farrell, Damien, Huang, Yong, Baker, Nathan A., & Nielsen, Jens E. On the development of protein pKa calculation algorithms. United States. doi:10.1002/prot.23091.
Carstensen, Tommy, Farrell, Damien, Huang, Yong, Baker, Nathan A., and Nielsen, Jens E. 2011. "On the development of protein pKa calculation algorithms". United States. doi:10.1002/prot.23091.
@article{osti_1037531,
title = {On the development of protein pKa calculation algorithms},
author = {Carstensen, Tommy and Farrell, Damien and Huang, Yong and Baker, Nathan A. and Nielsen, Jens E.},
abstractNote = {Protein pKa calculation algorithms are typically developed to reproduce experimental pKa values and provide us with a better understanding of the fundamental importance of electrostatics for protein structure and function. However, the approximations and adjustable parameters employed in almost all pKa calculation methods means that there is the risk that pKa calculation algorithms are 'over-fitted' to the available datasets, and that these methods therefore do not model protein physics realistically. We employ simulations of the protein pKa calculation algorithm development process to show that careful optimization procedures and non-biased experimental datasets must be applied to ensure a realistic description of the underlying physical terms. We furthermore investigate the effect of experimental noise and find a significant effect on the pKa calculation algorithm optimization landscape. Finally, we comment on strategies for ensuring the physical realism of protein pKa calculation algorithms and we assess the overall state of the field with a view to predicting future directions of development.},
doi = {10.1002/prot.23091},
journal = {Proteins. Structure, Function, and Bioinformatics},
number = 12,
volume = 79,
place = {United States},
year = 2011,
month =
}
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