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

Research output: Contribution to journalArticle

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 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.

Details

Authors
Organisations
External organisations
  • University of Cartagena
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
  • Other Medical Sciences not elsewhere specified

Keywords

  • Alzheimer, BACE1, G-score, GROMACS, Hydroxyethylamine, Molecular dynamics, Population density, Protonation state, Reduced amide, Tertiary carbinamine, TMoLiC
Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalJournal of Molecular Graphics and Modelling
Volume85
Publication statusPublished - 2018 Oct 1
Publication categoryResearch
Peer-reviewedYes