Exploring the pH- and Ligand-Dependent Flap Dynamics of Malarial Plasmepsin II.

ABSTRACT: Malaria remains a global health threat─over 400,000 deaths occurred in 2019. Plasmepsins are promising targets of antimalarial therapeutics; however, no inhibitors have reached the clinic. To fuel the progress, a detailed understanding of the pH- and ligand-dependent conformational dynamics of plasmepsins is needed. Here we present the continuous constant pH molecular dynamics study of the prototypical plasmepsin II and its complexed form with a substrate analogue. The simulations revealed that the catalytic dyads D34 and D214 are highly coupled in the apo protein and that the pepstatin binding enhances the difference in proton affinity, making D34 the general base and D214 the general acid. The simulations showed that the flap adopts an open state regardless of pH; however, upon pepstatin

SUBMITTER: Henderson JA 

PROVIDER: S-EPMC8812262 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature