Diffuse large B-cell lymphoma (DLBCL), a particularly aggressive cancer, is the most common Non-Hodgkin’s lymphoma found among adult patients. DLBCL is fatal if left untreated. Approximately 40% of patients either have a treatment resistant form of the cancer or relapse after treatment. FOX01 is a human forkhead transcription factor involved in regulating hematopoiesis. Mutations in this protein have been found in DLBCL patient’s cell lines and associated with decreased survival in DLBCL patients. The loss of function associated with these disease mutations is poorly understood. Thermal stability assays for some mutations show up to a 10 degree decrease in melting temperature (e.g. A166G and L183P), while other mutants (e.g. S205N and K171E) show no change from wild type. To understand how mutations might perturb FOX01 folding, we performed GPU-accelerated <i>ab initio</i> folding simulations on the distributed computing platform Folding@home. In the absence of experimental folding kinetics, comparative contact order analysis suggested that FOX01 folds on the order of tens of microseconds, making GPU simulation a tractable approach. Initial starting conformations were selected from cluster centers of MD simulations performed at 300K, 400K, 450K, and 498K, to produce ensembles of trajectories which we analyzed using a Markov State Model (MSM) approach. We discuss the predictions of the MSM, which later will be compared with similar <i>ab initio</i> binding simulations of FOX01 to DNA. Understanding how mutations affect the regulatory function of this transcription factor will help elucidate the role of FOX01 in the development of DLBCL and may provide insight for the development of new therapeutics.

FOX01 transcription factor folding landscape elucidates the role of disease mutations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.