title: Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California. Electronic address: vincent.t.metzger@gmail.com.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Metzger
authors.affiliation: Howard Hughes Medical Institute, University of California San Diego, La Jolla, California. Electronic address: changsun.eun@gmail.com.
authors.forename: Changsun
authors.initials: C
authors.lastname: Eun
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
authors.affiliation: Howard Hughes Medical Institute, University of California San Diego, La Jolla, California.
authors.forename: Gary
authors.initials: G
authors.lastname: Huber
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California; Howard Hughes Medical Institute, University of California San Diego, La Jolla, California; Department of Pharmacology, University of California San Diego, La Jolla, California.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D020134:Catalytic Domain; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology*; D012997:Solvents / Q000737:chemistry; D013045:Species Specificity; D055672:Static Electricity; D013499:Surface Properties; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D009097:Multienzyme Complexes; D012997:Solvents; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase