Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Wednesday Speaker Abstracts

MOLECULAR SIMULATIONS OF DISORDERED AND FLEXIBLE PROTEINS Sarah Rauscher ; 1 University of Toronto Mississauga, Chemical and Physical Sciences, Mississauga, ON, Canada

2 University of Toronto, Physics, Toronto, ON, Canada 3 University of Toronto, Chemistry, Toronto, ON, Canada

The STAT (signal transducer and activator of transcription) protein family is an important therapeutic target in leukemia and lymphoma. However, the lack of structural and dynamic information on STAT proteins limit drug design efforts. Cancer activating mutations located in the SH2 domain of STAT5B, including N642H, are observed clinically and the molecular basis for their increased oncogenicity is not currently known. Additionally, patients with the N642H mutation are reported to have increased drug resistance and poor response to chemotherapy. Here, we used molecular dynamics simulations to elucidate the dynamics of the wild type and an oncogenic mutant of human STAT5B protein, and to provide a molecular basis for the increased oncogenicity. We carried out extensive atomistic simulations of the wild type and mutant STAT5B proteins. The N642H mutation (i) led to a more rigid SH2 domain; (ii) significantly affected the size and dynamics of the peptide binding pockets; and (iii) increased the intra-SH2 domain interactions. The structural and dynamic information uncovered in this work may facilitate the design of small molecule drugs targeting the cancer activating mutants of STAT5B.

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