PhD Scientific Days 2024

Poster Session F - Molecular Medicine 3.

Delving Deep: Enhanced Insights from Molecular Dynamic Simulations of Complexed SULT1A1 Dimers

Text of the abstract

Our project aims to elucidate the diverse mechanisms guiding the selectivity of Sulfotransferase enzymes (SULTs). These phase II metabolizing enzymes catalyze sulfate transfers from their co-factor 3′-Phosphoadenosine 5′-Phosphosulfate (PAPS) to various substrates, thereby facilitating the elimination of diverse molecules such as drugs, hormones, and neurotransmitters. In our previous studies we have explored key differences of the SULT isoforms, however a deeper clarification of the basic mechanisms of these enzymes are still an ongoing effort in the field.
We strongly suspect that dimerization, a well-known attribute of these enzymes are playing a key role in unraveling these mechanisms, which was inadequately explored in previous studies.
For this end, we use multiple in silico methods, like molecular dynamics (MD) simulations, molecular docking and force distribution analysis (FDA), specifically focusing on dimer systems. By including the cofactor PAPS and a known large substrate, fulvestrant, we could explore an extended range of the conformational space of SULT1A1 dimers, shedding new light on the structural dynamics of the systems under study.
These results can be helpful in the future to develop an algorithm for machine learning, that could differentiate and even predict new substrates, thus helping in the development of ADME-Tox profiling of novel drug candidates and xenobiotics.
This project was funded by the Ministry for Innovation and Technology in Hungary (TKP2021 EGA 23), Ministére francais de l’Europe et des Affaires Etrangéres (2021-0143339), and Tét-Balaton project „drug-drug interactions of sulfotransferases” ( 2019-2.1.11-TÉT-2020-00096 ).