Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies

Dima A. Sabbah, Haizhen Andrew Zhong

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.

Original languageEnglish (US)
Pages (from-to)206-215
Number of pages10
JournalJournal of Molecular Graphics and Modelling
Volume68
DOIs
StatePublished - Jul 1 2016

Fingerprint

Amyloid Precursor Protein Secretases
Protonation
Molecular dynamics
molecular dynamics
inhibitors
Computer simulation
proteins
Proteins
simulation
Conformations
tactics
Aspartic Acid Proteases
aspartates
protease
Binding sites
Amyloid
Aspartic Acid
Peptides
peptides
brain

Keywords

  • Alzheimer's disease
  • BACE1
  • Molecular docking
  • Molecular dynamic simulation
  • Protonation state
  • β-secretase

ASJC Scopus subject areas

  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Computer Graphics and Computer-Aided Design
  • Materials Chemistry

Cite this

@article{76b46ae4fbb74402bb7554c57807a5d7,
title = "Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies",
abstract = "β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.",
keywords = "Alzheimer's disease, BACE1, Molecular docking, Molecular dynamic simulation, Protonation state, β-secretase",
author = "Sabbah, {Dima A.} and Zhong, {Haizhen Andrew}",
year = "2016",
month = "7",
day = "1",
doi = "10.1016/j.jmgm.2016.07.005",
language = "English (US)",
volume = "68",
pages = "206--215",
journal = "Journal of Molecular Graphics and Modelling",
issn = "1093-3263",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies

AU - Sabbah, Dima A.

AU - Zhong, Haizhen Andrew

PY - 2016/7/1

Y1 - 2016/7/1

N2 - β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.

AB - β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is −1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors.

KW - Alzheimer's disease

KW - BACE1

KW - Molecular docking

KW - Molecular dynamic simulation

KW - Protonation state

KW - β-secretase

UR - http://www.scopus.com/inward/record.url?scp=84979644215&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979644215&partnerID=8YFLogxK

U2 - 10.1016/j.jmgm.2016.07.005

DO - 10.1016/j.jmgm.2016.07.005

M3 - Article

C2 - 27474865

AN - SCOPUS:84979644215

VL - 68

SP - 206

EP - 215

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

SN - 1093-3263

ER -