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Flap Dynamics in Pepsin-Like Aspartic Proteases : A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems

Bhakat, Soumendranath LU and Söderhjelm, Pär LU (2022) In Journal of Chemical Information and Modeling 62(4). p.914-926
Abstract

The flexibility of β hairpin structure known as the flap plays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequential similarity. In this study, we have used apo Plm-II and BACE-1 as model systems. In the apo form of the proteases, a conserved tyrosine residue in the flap region remains in a dynamic equilibrium between the normal and flipped states through rotation of the χ1 and χ2 angles. Independent MD simulations of Plm-II and BACE-1 remained stuck either in the normal or flipped state. Metadynamics simulations using side-chain torsion angles (χ1 and χ2 of tyrosine) as collective variables sampled the... (More)

The flexibility of β hairpin structure known as the flap plays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequential similarity. In this study, we have used apo Plm-II and BACE-1 as model systems. In the apo form of the proteases, a conserved tyrosine residue in the flap region remains in a dynamic equilibrium between the normal and flipped states through rotation of the χ1 and χ2 angles. Independent MD simulations of Plm-II and BACE-1 remained stuck either in the normal or flipped state. Metadynamics simulations using side-chain torsion angles (χ1 and χ2 of tyrosine) as collective variables sampled the transition between the normal and flipped states. Qualitatively, the two states were predicted to be equally populated. The normal and flipped states were stabilized by H-bond interactions to a tryptophan residue and to the catalytic aspartate, respectively. Further, mutation of tyrosine to an amino-acid with smaller side-chain, such as alanine, reduced the flexibility of the flap and resulted in a flap collapse (flap loses flexibility and remains stuck in a particular state). This is in accordance with previous experimental studies, which showed that mutation to alanine resulted in loss of activity in pepsin-like aspartic proteases. Our results suggest that the ring flipping associated with the tyrosine side-chain is the key order parameter that governs flap dynamics and opening of the binding pocket in most pepsin-like aspartic proteases.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Information and Modeling
volume
62
issue
4
pages
13 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:35138093
  • scopus:85124890158
ISSN
1549-9596
DOI
10.1021/acs.jcim.1c00840
language
English
LU publication?
yes
id
8655232a-1f0d-4f2b-aa21-e05a3ed8fe18
date added to LUP
2022-05-20 11:11:24
date last changed
2024-04-18 08:10:53
@article{8655232a-1f0d-4f2b-aa21-e05a3ed8fe18,
  abstract     = {{<p>The flexibility of β hairpin structure known as the flap plays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequential similarity. In this study, we have used apo Plm-II and BACE-1 as model systems. In the apo form of the proteases, a conserved tyrosine residue in the flap region remains in a dynamic equilibrium between the normal and flipped states through rotation of the χ<sub>1</sub> and χ<sub>2</sub> angles. Independent MD simulations of Plm-II and BACE-1 remained stuck either in the normal or flipped state. Metadynamics simulations using side-chain torsion angles (χ<sub>1</sub> and χ<sub>2</sub> of tyrosine) as collective variables sampled the transition between the normal and flipped states. Qualitatively, the two states were predicted to be equally populated. The normal and flipped states were stabilized by H-bond interactions to a tryptophan residue and to the catalytic aspartate, respectively. Further, mutation of tyrosine to an amino-acid with smaller side-chain, such as alanine, reduced the flexibility of the flap and resulted in a flap collapse (flap loses flexibility and remains stuck in a particular state). This is in accordance with previous experimental studies, which showed that mutation to alanine resulted in loss of activity in pepsin-like aspartic proteases. Our results suggest that the ring flipping associated with the tyrosine side-chain is the key order parameter that governs flap dynamics and opening of the binding pocket in most pepsin-like aspartic proteases.</p>}},
  author       = {{Bhakat, Soumendranath and Söderhjelm, Pär}},
  issn         = {{1549-9596}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{4}},
  pages        = {{914--926}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Chemical Information and Modeling}},
  title        = {{Flap Dynamics in Pepsin-Like Aspartic Proteases : A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems}},
  url          = {{http://dx.doi.org/10.1021/acs.jcim.1c00840}},
  doi          = {{10.1021/acs.jcim.1c00840}},
  volume       = {{62}},
  year         = {{2022}},
}