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Conformational Dynamics of Plasmepsin X during Inhibitor Binding.
Wilson Karubiu1, Richard Kullmann1, Michael Krummhaar1
1Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, Potsdam 14476, Germany.
The Journal of Physical Chemistry. B
|May 13, 2026
Summary
Malaria drug targets, plasmepsin X (PMX) inhibitors WM382 and WM4, are positively charged. Molecular dynamics simulations reveal inhibitor unbinding is coupled to flap conformational changes in PMX.
Area of Science:
- Biochemistry
- Parasitology
- Structural Biology
Background:
- Aspartic protease plasmepsin X (PMX) from Plasmodium is a key target for malaria drug development.
- WM382 and WM4 are potent PMX inhibitors featuring a guanidinium group crucial for binding.
- Standard depictions often show the guanidinium group as uncharged, but pKa predictions suggest it is protonated and positively charged in bound complexes.
Purpose of the Study:
- To investigate the protonation state of PMX inhibitors and its impact on binding.
- To explore the dynamic interplay between PMX conformational changes and inhibitor unbinding using molecular dynamics.
Main Methods:
- Hamiltonian replica exchange molecular dynamics (H-REMD) simulations were employed.
- Simulations were initiated from the predicted protonated state of the PMX-WM382 complex.
- Analysis focused on unbinding pathways and associated conformational dynamics of PMX.
Main Results:
- pKa predictions indicated that the guanidinium groups of WM382 and WM4 are positively charged when bound to PMX.
- H-REMD simulations identified eight unbinding pathways, with a dominant route observed.
- Inhibitor unbinding was strongly coupled to conformational transitions of the PMX flap, moving from a closed to an open state.
Conclusions:
- The positive charge of the inhibitor's guanidinium group is counterbalanced by a negatively charged catalytic aspartate (D266) in PMX.
- The flap region of PMX plays a critical role in regulating inhibitor binding and release.
- Upon unbinding, the flap adopts an occluded conformation, potentially preventing re-binding or blocking the active site.
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