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Issue 4, 2015
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Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics

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Abstract

Herein, for the first time, we report the flap opening and closing in Plasmepsin proteases – plasmepsin II (PlmII) was used as a prototype model. We proposed different combined parameters to define the asymmetric flap motion; the distance, d1, between the flap tip residues (Val78 and Leu292); the dihedral angle, ϕ; in addition to TriCα angles Val78–Asp34–Leu292, θ1, and Val78–Asp214–Leu292, θ2. Only three combined parameters, the distance, d1, the dihedral angle, ϕ, and the TriCα angle, θ1, were found to appropriately define the observed “twisting’ motion during the flap opening and closing. The coordinated motions of the proline-rich loop adjacent to the binding cavity rim appeared to exert steric hindrance on the flap residues, driving the flap away from the active site cavity. This loop may also have increased movements around the catalytic dyad residue, Asp214, making TriCα, θ2, unreliable in describing the flap motion. The full flap opening at d1, 23.6 Å, corresponded to the largest TriCα angle, θ1, at 78.6° on a ∼46 ns time scale. Overall the average θ1 and θ2 for the bound was ∼46° and ∼53°, respectively, compared to ∼50° and ∼59° for the Apo PlmII, indicating a drastic increase in TriCα as the active site cavity opens. Similar trends in the distance, d1, and the dihedral angle, ϕ, were observed during the simulation. The asymmetrical opening of the binding cavity was best described by the large shift in ϕ from −33.91° to +21.00° corresponding to the partial opening of the flap in the range of 22–31 ns. Though, the dihedral angle described the twisting of the flap, the extent of flap opening can appropriately be defined by combining d1 and θ1. The results presented here, on the combined parameters, will certainly augment current efforts in designing potent structure-based inhibitors against plasmepsins.

Graphical abstract: Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics

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Supplementary files

Article information


Submitted
24 Oct 2014
Accepted
23 Jan 2015
First published
23 Jan 2015

Mol. BioSyst., 2015,11, 1061-1066
Article type
Paper
Author version available

Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics

W. Karubiu, S. Bhakat, L. McGillewie and M. E. S. Soliman, Mol. BioSyst., 2015, 11, 1061
DOI: 10.1039/C4MB00631C

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