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Transferability of conformational dependent charges from protein simulations

Genheden, Samuel LU ; Söderhjelm, Pär LU and Ryde, Ulf LU (2012) In International Journal of Quantum Chemistry 112(7). p.1768-1785
Abstract
We have studied the transferability of atomic charges for proteins, fitted to the quantum mechanical electrostatic potential and extensively averaged over a set of structures sampled by molecular dynamics (MD) and over all residues of the same kind in the protein sequence (xAvESP). Previously, such charges were obtained for one single protein (avidin). In this study, we use five additional proteins. The aim of this study is fourfold. First, we provide xAvESP charges for all amino acids, including amino- and carboxy-terminal variants of all, as well as alternative protonation states of His, Asp, Glu, Lys, Arg, Cys, and Tyr. Second, we show that the xAvESP charges averaged over the five new proteins are similar to charges obtained in the... (More)
We have studied the transferability of atomic charges for proteins, fitted to the quantum mechanical electrostatic potential and extensively averaged over a set of structures sampled by molecular dynamics (MD) and over all residues of the same kind in the protein sequence (xAvESP). Previously, such charges were obtained for one single protein (avidin). In this study, we use five additional proteins. The aim of this study is fourfold. First, we provide xAvESP charges for all amino acids, including amino- and carboxy-terminal variants of all, as well as alternative protonation states of His, Asp, Glu, Lys, Arg, Cys, and Tyr. Second, we show that the xAvESP charges averaged over the five new proteins are similar to charges obtained in the same way for avidin, with a correlation coefficient of 0.997. This shows that the charges are transferable and system-independent. Electrostatic proteinligand interaction energies calculated with charges obtained from different proteins differ by only 13 kJ/mol on average. The xAvESP charges correlate rather well with Amber charges (except for the N atom of amino-terminal residues that are erroneous in Amber), although they are obtained in a more general way. Third, the conformational dependence of the charges is significant and gives rise to quite large differences in energies. However, these differences are to a large extent screened by solvation effects. For example, the solvent-screened electrostatic interaction energy between the protein galectin-3 and five different ligands varies with the charge sets by less than 3 kJ/mol on average. Finally, we show that the xAvESP charges give a comparable root-mean-squared deviation as the Amber charges for the MD simulations of 18 proteinligand complexes, they give comparable or slightly worse backbone N?H order parameters for two galectin-3 complexes, but they give a better correlation between calculated and experimental affinities for the binding of seven biotin analogues to avidin and for nine inhibitors of factor Xa. (c) 2011 Wiley Periodicals, Inc. Int J Quantum Chem 112:17681785, 2012 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
conformation dependence, generalized Born solvation, GBSA, MM, molecular dynamics simulations, electrostatic potential charges
in
International Journal of Quantum Chemistry
volume
112
issue
7
pages
1768 - 1785
publisher
John Wiley & Sons
external identifiers
  • wos:000300503100002
  • scopus:84857277947
ISSN
0020-7608
DOI
10.1002/qua.22967
language
English
LU publication?
yes
id
ff00055f-fd18-4d82-a599-a3310cdc76f9 (old id 2516987)
date added to LUP
2012-05-08 13:19:22
date last changed
2017-01-01 03:37:26
@article{ff00055f-fd18-4d82-a599-a3310cdc76f9,
  abstract     = {We have studied the transferability of atomic charges for proteins, fitted to the quantum mechanical electrostatic potential and extensively averaged over a set of structures sampled by molecular dynamics (MD) and over all residues of the same kind in the protein sequence (xAvESP). Previously, such charges were obtained for one single protein (avidin). In this study, we use five additional proteins. The aim of this study is fourfold. First, we provide xAvESP charges for all amino acids, including amino- and carboxy-terminal variants of all, as well as alternative protonation states of His, Asp, Glu, Lys, Arg, Cys, and Tyr. Second, we show that the xAvESP charges averaged over the five new proteins are similar to charges obtained in the same way for avidin, with a correlation coefficient of 0.997. This shows that the charges are transferable and system-independent. Electrostatic proteinligand interaction energies calculated with charges obtained from different proteins differ by only 13 kJ/mol on average. The xAvESP charges correlate rather well with Amber charges (except for the N atom of amino-terminal residues that are erroneous in Amber), although they are obtained in a more general way. Third, the conformational dependence of the charges is significant and gives rise to quite large differences in energies. However, these differences are to a large extent screened by solvation effects. For example, the solvent-screened electrostatic interaction energy between the protein galectin-3 and five different ligands varies with the charge sets by less than 3 kJ/mol on average. Finally, we show that the xAvESP charges give a comparable root-mean-squared deviation as the Amber charges for the MD simulations of 18 proteinligand complexes, they give comparable or slightly worse backbone N?H order parameters for two galectin-3 complexes, but they give a better correlation between calculated and experimental affinities for the binding of seven biotin analogues to avidin and for nine inhibitors of factor Xa. (c) 2011 Wiley Periodicals, Inc. Int J Quantum Chem 112:17681785, 2012},
  author       = {Genheden, Samuel and Söderhjelm, Pär and Ryde, Ulf},
  issn         = {0020-7608},
  keyword      = {conformation dependence,generalized Born solvation,GBSA,MM,molecular dynamics simulations,electrostatic potential charges},
  language     = {eng},
  number       = {7},
  pages        = {1768--1785},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Quantum Chemistry},
  title        = {Transferability of conformational dependent charges from protein simulations},
  url          = {http://dx.doi.org/10.1002/qua.22967},
  volume       = {112},
  year         = {2012},
}