Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.

TitleElectrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.
Publication TypeJournal Article
Year of Publication2014
JournalBiophysical journal
Volume107
Issue10
Pagination2394-402
Date Published2014
ISSN0006-3495
Abstract

We perform Brownian dynamics simulations and Smoluchowski continuum modeling of the bifunctional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (P. falciparum DHFR-TS) with the objective of understanding the electrostatic channeling of dihydrofolate generated at the TS active site to the DHFR active site. The results of Brownian dynamics simulations and Smoluchowski continuum modeling suggest that compared to Leishmania major DHFR-TS, P. falciparum DHFR-TS has a lower but significant electrostatic-mediated channeling efficiency (?15-25%) at physiological pH (7.0) and ionic strength (150 mM). We also find that removing the electric charges from key basic residues located between the DHFR and TS active sites significantly reduces the channeling efficiency of P. falciparum DHFR-TS. Although several protozoan DHFR-TS enzymes are known to have similar tertiary and quaternary structure, subtle differences in structure, active-site geometry, and charge distribution appear to influence both electrostatic-mediated and proximity-based substrate channeling.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0006-3495(14)01048-0
DOI10.1016/j.bpj.2014.09.039
Short TitleBiophys J
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