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G-score : A function to solve the puzzle of modeling the protonation states of β-secretase binding pocket

Gueto-Tettay, Carlos LU ; Martinez-Consuegra, Alejandro ; Pelaez-Bedoya, Luis and Drosos-Ramirez, Juan Carlos (2018) In Journal of Molecular Graphics and Modelling 85. p.1-12
Abstract

The population density concept has emerged as a proposal for the analysis of molecular dynamics results, the key characteristic of population density is the evaluation of the simultaneous occurrence of a set of relevant parameters for a system. However, despite its statistical strength, selection of the tolerance level for the comparison of different models may appear as arbitrary. This work introduces the G-score, a function which summarizes and categorizes the results of population density analysis. Additionally, it incorporates parameters based on rmsd and dihedral angles, besides the protein-protein and protein-ligand interatomic distances conventionally used, which complement each other to provide a better description of the... (More)

The population density concept has emerged as a proposal for the analysis of molecular dynamics results, the key characteristic of population density is the evaluation of the simultaneous occurrence of a set of relevant parameters for a system. However, despite its statistical strength, selection of the tolerance level for the comparison of different models may appear as arbitrary. This work introduces the G-score, a function which summarizes and categorizes the results of population density analysis. Additionally, it incorporates parameters based on rmsd and dihedral angles, besides the protein-protein and protein-ligand interatomic distances conventionally used, which complement each other to provide a better description of the behavior of the system. These newly-proposed tools were applied to determine the most probable protonation state of the aspartic dyad of BACE1, Asp93 and Asp289, in the presence of three types of transition state inhibitors namely: reduced amides, tertiary carbinamines and hydroxyethylamines. The results show a full agreement between G-score values and population density charts, with the advantage of allowing a quick and direct comparison among all the considered models. We anticipate that the simplicity of calculating the parameters employed in this study will permit the extensive use of population density and the G-score for other molecular systems.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer, BACE1, G-score, GROMACS, Hydroxyethylamine, Molecular dynamics, Population density, Protonation state, Reduced amide, Tertiary carbinamine, TMoLiC
in
Journal of Molecular Graphics and Modelling
volume
85
pages
12 pages
publisher
Elsevier
external identifiers
  • scopus:85050182704
  • pmid:30053756
ISSN
1093-3263
DOI
10.1016/j.jmgm.2018.07.008
language
English
LU publication?
yes
id
b649dcdc-0c72-45dc-ae50-009af1f1a489
date added to LUP
2018-08-15 08:09:35
date last changed
2021-04-20 05:42:42
@article{b649dcdc-0c72-45dc-ae50-009af1f1a489,
  abstract     = {<p>The population density concept has emerged as a proposal for the analysis of molecular dynamics results, the key characteristic of population density is the evaluation of the simultaneous occurrence of a set of relevant parameters for a system. However, despite its statistical strength, selection of the tolerance level for the comparison of different models may appear as arbitrary. This work introduces the G-score, a function which summarizes and categorizes the results of population density analysis. Additionally, it incorporates parameters based on rmsd and dihedral angles, besides the protein-protein and protein-ligand interatomic distances conventionally used, which complement each other to provide a better description of the behavior of the system. These newly-proposed tools were applied to determine the most probable protonation state of the aspartic dyad of BACE1, Asp93 and Asp289, in the presence of three types of transition state inhibitors namely: reduced amides, tertiary carbinamines and hydroxyethylamines. The results show a full agreement between G-score values and population density charts, with the advantage of allowing a quick and direct comparison among all the considered models. We anticipate that the simplicity of calculating the parameters employed in this study will permit the extensive use of population density and the G-score for other molecular systems.</p>},
  author       = {Gueto-Tettay, Carlos and Martinez-Consuegra, Alejandro and Pelaez-Bedoya, Luis and Drosos-Ramirez, Juan Carlos},
  issn         = {1093-3263},
  language     = {eng},
  month        = {10},
  pages        = {1--12},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Graphics and Modelling},
  title        = {G-score : A function to solve the puzzle of modeling the protonation states of β-secretase binding pocket},
  url          = {http://dx.doi.org/10.1016/j.jmgm.2018.07.008},
  doi          = {10.1016/j.jmgm.2018.07.008},
  volume       = {85},
  year         = {2018},
}