General information
Offer title : M/F Thesis on modeling the impact of mutations on the structure and activity of Plasmodium falciparum dihydropterate synthase (H/F)
Reference : UPR8001-MARBRU-004
Number of position : 1
Workplace : TOULOUSE
Date of publication : 16 April 2025
Type of Contract : FTC PhD student / Offer for thesis
Contract Period : 36 months
Start date of the thesis : 1 September 2025
Proportion of work : Full Time
Remuneration : 2200 gross monthly
Section(s) CN : 20 - Molecular and structural biology, biochemistry
Description of the thesis topic
Gestational malaria remains a major public health problem, responsible for significant morbidity and mortality in both pregnant women and fetuses. In addition to vector protection measures, the sulfadoxine-pyrimethamine (SP) combination is used throughout sub-Saharan Africa for intermittent preventive treatment (IPT) in pregnant women. SP blocks the folate biosynthesis pathway, by inhibiting two enzymes: dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), respectively. However,
its efficacy is threatened by the appearance of mutations in the genes coding for DHFR and DHPS in Plasmodium falciparum. A new PfDHPS mutation, I431V, was identified in Nigeria in 2007, then in Cameroon in 2010. This mutation was mainly found in association with 4 other PfDHPS mutations (S436A, A437G, A581G and A613S), forming a quintuple vagKgs mutant. Analogy with some highly mutated genotypes suggests that this PfDHPS quintuple mutant may have a high level of sulfadoxine resistance. To date, few data are available concerning this I431V mutation.
The aim of the project of which this thesis is a part is to understand the role and impact of this new I431V mutation of PfDHPS, and the associated mutants. To answer this question, joint studies are being carried out on epidemiology, phenotype and enzyme/substrate molecular interactions. The latter is where our simulation activities come into play. They are threefold: i) exploration of enzyme structure and dynamics (classical DM); ii) study of enzyme activity (QMM DM); iii) docking of new molecules, taking into account the impact of the mutations explored. This thesis will cover in particular the last 2 aspects.
Work Context
The candidate will have a solid background in physics or computational chemistry and QMM techniques adapted to biomolecules. Knowledge of in silico screening is a plus.
The position is located in a sector under the protection of scientific and technical potential (PPST), and therefore requires, in accordance with the regulations, that your arrival is authorized by the competent authority of the MESR.
Constraints and risks
None.